Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400
Abstract Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human $ Na^{+} $/$ Ca^{2+} $ exchanger NCX1.3 in the presence of a specific inhibit...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Dong, Yanli [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2023 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2023 |
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| Übergeordnetes Werk: |
Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 43(2023), 1 vom: 15. Dez., Seite 14-31 |
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| Übergeordnetes Werk: |
volume:43 ; year:2023 ; number:1 ; day:15 ; month:12 ; pages:14-31 |
| Links: |
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| DOI / URN: |
10.1038/s44318-023-00013-0 |
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| Katalog-ID: |
SPR054273986 |
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| 041 | |a eng | ||
| 100 | 1 | |a Dong, Yanli |e verfasserin |0 (orcid)0000-0002-7919-3276 |4 aut | |
| 245 | 1 | 0 | |a Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400 |
| 264 | 1 | |c 2023 | |
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| 337 | |a Computermedien |b c |2 rdamedia | ||
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| 500 | |a © The Author(s) 2023 | ||
| 520 | |a Abstract Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human $ Na^{+} $/$ Ca^{2+} $ exchanger NCX1.3 in the presence of a specific inhibitor, SEA0400. Conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. We show how regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and predicted to clash with gating helices $ TMs^{1/6} $ at the outward-facing state, thus hindering conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating $ Ca^{2+} $-uptake activity of NCX1.3. | ||
| 520 | |a Synopsis The exchange of sodium and calcium ions across membranes plays important (patho)physiological roles. Here, cryo-EM is used to study the inhibitor-bound human sodium-calcium exchanger NCX1.3, shedding light on the molecular mechanisms underlying SEA0400- and XIP-mediated inactivation. The XIP region is located within a groove between TMD and CBD2, mediating inactivation by obstructing the conformational transition of gating helices $ TMs^{1/6} $.An SEA0400 molecule is situated within a negatively charged cavity in the transmembrane region, exerting allosteric inhibition by inhibiting the conformational changes of TM2ab.The XIP and SEA0400, though not directly interacting, mutually stabilize each other’s binding pockets in the inward-facing conformation through loopTM1-2, thereby cooperatively inhibiting the $ Ca^{2 +} $-uptake activity of NCX.Allosteric inhibition by SEA0400 is selectively effective in the antiporter’s reverse mode. | ||
| 520 | |a Cryo-EM data show how two key endogenous and exogenous sodium/calcium ion-exchange inhibitors block conformational rearrangements associated with ion exchange by NCX1.3. | ||
| 650 | 4 | |a Sodium-calcium Exchanger |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Calcium Homeostasis |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Allosteric Inhibition |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a SEA0400 |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Exchanger Inhibitory Peptide (XIP) |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Yu, Zhuoya |4 aut | |
| 700 | 1 | |a Li, Yue |0 (orcid)0000-0002-1211-7383 |4 aut | |
| 700 | 1 | |a Huang, Bo |4 aut | |
| 700 | 1 | |a Bai, Qinru |4 aut | |
| 700 | 1 | |a Gao, Yiwei |0 (orcid)0000-0001-8169-9332 |4 aut | |
| 700 | 1 | |a Chen, Qihao |4 aut | |
| 700 | 1 | |a Li, Na |4 aut | |
| 700 | 1 | |a He, Lingli |4 aut | |
| 700 | 1 | |a Zhao, Yan |0 (orcid)0000-0002-4348-256X |4 aut | |
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| 773 | 1 | 8 | |g volume:43 |g year:2023 |g number:1 |g day:15 |g month:12 |g pages:14-31 |
| 856 | 4 | 0 | |u https://dx.doi.org/10.1038/s44318-023-00013-0 |z kostenfrei |3 Volltext |
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| 912 | |a GBV_ILN_2015 | ||
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| 912 | |a GBV_ILN_2021 | ||
| 912 | |a GBV_ILN_2025 | ||
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| 912 | |a GBV_ILN_2027 | ||
| 912 | |a GBV_ILN_2034 | ||
| 912 | |a GBV_ILN_2037 | ||
| 912 | |a GBV_ILN_2038 | ||
| 912 | |a GBV_ILN_2044 | ||
| 912 | |a GBV_ILN_2048 | ||
| 912 | |a GBV_ILN_2049 | ||
| 912 | |a GBV_ILN_2050 | ||
| 912 | |a GBV_ILN_2055 | ||
| 912 | |a GBV_ILN_2056 | ||
| 912 | |a GBV_ILN_2057 | ||
| 912 | |a GBV_ILN_2059 | ||
| 912 | |a GBV_ILN_2061 | ||
| 912 | |a GBV_ILN_2064 | ||
| 912 | |a GBV_ILN_2068 | ||
| 912 | |a GBV_ILN_2088 | ||
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| 912 | |a GBV_ILN_2113 | ||
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| 912 | |a GBV_ILN_2119 | ||
| 912 | |a GBV_ILN_2122 | ||
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| 912 | |a GBV_ILN_2143 | ||
| 912 | |a GBV_ILN_2144 | ||
| 912 | |a GBV_ILN_2147 | ||
| 912 | |a GBV_ILN_2148 | ||
| 912 | |a GBV_ILN_2152 | ||
| 912 | |a GBV_ILN_2153 | ||
| 912 | |a GBV_ILN_2190 | ||
| 912 | |a GBV_ILN_2232 | ||
| 912 | |a GBV_ILN_2336 | ||
| 912 | |a GBV_ILN_2470 | ||
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| 912 | |a GBV_ILN_2507 | ||
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| 912 | |a GBV_ILN_4035 | ||
| 912 | |a GBV_ILN_4037 | ||
| 912 | |a GBV_ILN_4046 | ||
| 912 | |a GBV_ILN_4112 | ||
| 912 | |a GBV_ILN_4125 | ||
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10.1038/s44318-023-00013-0 doi (DE-627)SPR054273986 (SPR)s44318-023-00013-0-e DE-627 ger DE-627 rakwb eng Dong, Yanli verfasserin (orcid)0000-0002-7919-3276 aut Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human $ Na^{+} $/$ Ca^{2+} $ exchanger NCX1.3 in the presence of a specific inhibitor, SEA0400. Conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. We show how regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and predicted to clash with gating helices $ TMs^{1/6} $ at the outward-facing state, thus hindering conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating $ Ca^{2+} $-uptake activity of NCX1.3. Synopsis The exchange of sodium and calcium ions across membranes plays important (patho)physiological roles. Here, cryo-EM is used to study the inhibitor-bound human sodium-calcium exchanger NCX1.3, shedding light on the molecular mechanisms underlying SEA0400- and XIP-mediated inactivation. The XIP region is located within a groove between TMD and CBD2, mediating inactivation by obstructing the conformational transition of gating helices $ TMs^{1/6} $.An SEA0400 molecule is situated within a negatively charged cavity in the transmembrane region, exerting allosteric inhibition by inhibiting the conformational changes of TM2ab.The XIP and SEA0400, though not directly interacting, mutually stabilize each other’s binding pockets in the inward-facing conformation through loopTM1-2, thereby cooperatively inhibiting the $ Ca^{2 +} $-uptake activity of NCX.Allosteric inhibition by SEA0400 is selectively effective in the antiporter’s reverse mode. Cryo-EM data show how two key endogenous and exogenous sodium/calcium ion-exchange inhibitors block conformational rearrangements associated with ion exchange by NCX1.3. Sodium-calcium Exchanger (dpeaa)DE-He213 Calcium Homeostasis (dpeaa)DE-He213 Allosteric Inhibition (dpeaa)DE-He213 SEA0400 (dpeaa)DE-He213 Exchanger Inhibitory Peptide (XIP) (dpeaa)DE-He213 Yu, Zhuoya aut Li, Yue (orcid)0000-0002-1211-7383 aut Huang, Bo aut Bai, Qinru aut Gao, Yiwei (orcid)0000-0001-8169-9332 aut Chen, Qihao aut Li, Na aut He, Lingli aut Zhao, Yan (orcid)0000-0002-4348-256X aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2023), 1 vom: 15. Dez., Seite 14-31 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2023 number:1 day:15 month:12 pages:14-31 https://dx.doi.org/10.1038/s44318-023-00013-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 43 2023 1 15 12 14-31 |
| spelling |
10.1038/s44318-023-00013-0 doi (DE-627)SPR054273986 (SPR)s44318-023-00013-0-e DE-627 ger DE-627 rakwb eng Dong, Yanli verfasserin (orcid)0000-0002-7919-3276 aut Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human $ Na^{+} $/$ Ca^{2+} $ exchanger NCX1.3 in the presence of a specific inhibitor, SEA0400. Conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. We show how regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and predicted to clash with gating helices $ TMs^{1/6} $ at the outward-facing state, thus hindering conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating $ Ca^{2+} $-uptake activity of NCX1.3. Synopsis The exchange of sodium and calcium ions across membranes plays important (patho)physiological roles. Here, cryo-EM is used to study the inhibitor-bound human sodium-calcium exchanger NCX1.3, shedding light on the molecular mechanisms underlying SEA0400- and XIP-mediated inactivation. The XIP region is located within a groove between TMD and CBD2, mediating inactivation by obstructing the conformational transition of gating helices $ TMs^{1/6} $.An SEA0400 molecule is situated within a negatively charged cavity in the transmembrane region, exerting allosteric inhibition by inhibiting the conformational changes of TM2ab.The XIP and SEA0400, though not directly interacting, mutually stabilize each other’s binding pockets in the inward-facing conformation through loopTM1-2, thereby cooperatively inhibiting the $ Ca^{2 +} $-uptake activity of NCX.Allosteric inhibition by SEA0400 is selectively effective in the antiporter’s reverse mode. Cryo-EM data show how two key endogenous and exogenous sodium/calcium ion-exchange inhibitors block conformational rearrangements associated with ion exchange by NCX1.3. Sodium-calcium Exchanger (dpeaa)DE-He213 Calcium Homeostasis (dpeaa)DE-He213 Allosteric Inhibition (dpeaa)DE-He213 SEA0400 (dpeaa)DE-He213 Exchanger Inhibitory Peptide (XIP) (dpeaa)DE-He213 Yu, Zhuoya aut Li, Yue (orcid)0000-0002-1211-7383 aut Huang, Bo aut Bai, Qinru aut Gao, Yiwei (orcid)0000-0001-8169-9332 aut Chen, Qihao aut Li, Na aut He, Lingli aut Zhao, Yan (orcid)0000-0002-4348-256X aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2023), 1 vom: 15. Dez., Seite 14-31 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2023 number:1 day:15 month:12 pages:14-31 https://dx.doi.org/10.1038/s44318-023-00013-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 43 2023 1 15 12 14-31 |
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10.1038/s44318-023-00013-0 doi (DE-627)SPR054273986 (SPR)s44318-023-00013-0-e DE-627 ger DE-627 rakwb eng Dong, Yanli verfasserin (orcid)0000-0002-7919-3276 aut Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human $ Na^{+} $/$ Ca^{2+} $ exchanger NCX1.3 in the presence of a specific inhibitor, SEA0400. Conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. We show how regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and predicted to clash with gating helices $ TMs^{1/6} $ at the outward-facing state, thus hindering conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating $ Ca^{2+} $-uptake activity of NCX1.3. Synopsis The exchange of sodium and calcium ions across membranes plays important (patho)physiological roles. Here, cryo-EM is used to study the inhibitor-bound human sodium-calcium exchanger NCX1.3, shedding light on the molecular mechanisms underlying SEA0400- and XIP-mediated inactivation. The XIP region is located within a groove between TMD and CBD2, mediating inactivation by obstructing the conformational transition of gating helices $ TMs^{1/6} $.An SEA0400 molecule is situated within a negatively charged cavity in the transmembrane region, exerting allosteric inhibition by inhibiting the conformational changes of TM2ab.The XIP and SEA0400, though not directly interacting, mutually stabilize each other’s binding pockets in the inward-facing conformation through loopTM1-2, thereby cooperatively inhibiting the $ Ca^{2 +} $-uptake activity of NCX.Allosteric inhibition by SEA0400 is selectively effective in the antiporter’s reverse mode. Cryo-EM data show how two key endogenous and exogenous sodium/calcium ion-exchange inhibitors block conformational rearrangements associated with ion exchange by NCX1.3. Sodium-calcium Exchanger (dpeaa)DE-He213 Calcium Homeostasis (dpeaa)DE-He213 Allosteric Inhibition (dpeaa)DE-He213 SEA0400 (dpeaa)DE-He213 Exchanger Inhibitory Peptide (XIP) (dpeaa)DE-He213 Yu, Zhuoya aut Li, Yue (orcid)0000-0002-1211-7383 aut Huang, Bo aut Bai, Qinru aut Gao, Yiwei (orcid)0000-0001-8169-9332 aut Chen, Qihao aut Li, Na aut He, Lingli aut Zhao, Yan (orcid)0000-0002-4348-256X aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2023), 1 vom: 15. Dez., Seite 14-31 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2023 number:1 day:15 month:12 pages:14-31 https://dx.doi.org/10.1038/s44318-023-00013-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 43 2023 1 15 12 14-31 |
| allfieldsGer |
10.1038/s44318-023-00013-0 doi (DE-627)SPR054273986 (SPR)s44318-023-00013-0-e DE-627 ger DE-627 rakwb eng Dong, Yanli verfasserin (orcid)0000-0002-7919-3276 aut Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human $ Na^{+} $/$ Ca^{2+} $ exchanger NCX1.3 in the presence of a specific inhibitor, SEA0400. Conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. We show how regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and predicted to clash with gating helices $ TMs^{1/6} $ at the outward-facing state, thus hindering conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating $ Ca^{2+} $-uptake activity of NCX1.3. Synopsis The exchange of sodium and calcium ions across membranes plays important (patho)physiological roles. Here, cryo-EM is used to study the inhibitor-bound human sodium-calcium exchanger NCX1.3, shedding light on the molecular mechanisms underlying SEA0400- and XIP-mediated inactivation. The XIP region is located within a groove between TMD and CBD2, mediating inactivation by obstructing the conformational transition of gating helices $ TMs^{1/6} $.An SEA0400 molecule is situated within a negatively charged cavity in the transmembrane region, exerting allosteric inhibition by inhibiting the conformational changes of TM2ab.The XIP and SEA0400, though not directly interacting, mutually stabilize each other’s binding pockets in the inward-facing conformation through loopTM1-2, thereby cooperatively inhibiting the $ Ca^{2 +} $-uptake activity of NCX.Allosteric inhibition by SEA0400 is selectively effective in the antiporter’s reverse mode. Cryo-EM data show how two key endogenous and exogenous sodium/calcium ion-exchange inhibitors block conformational rearrangements associated with ion exchange by NCX1.3. Sodium-calcium Exchanger (dpeaa)DE-He213 Calcium Homeostasis (dpeaa)DE-He213 Allosteric Inhibition (dpeaa)DE-He213 SEA0400 (dpeaa)DE-He213 Exchanger Inhibitory Peptide (XIP) (dpeaa)DE-He213 Yu, Zhuoya aut Li, Yue (orcid)0000-0002-1211-7383 aut Huang, Bo aut Bai, Qinru aut Gao, Yiwei (orcid)0000-0001-8169-9332 aut Chen, Qihao aut Li, Na aut He, Lingli aut Zhao, Yan (orcid)0000-0002-4348-256X aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2023), 1 vom: 15. Dez., Seite 14-31 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2023 number:1 day:15 month:12 pages:14-31 https://dx.doi.org/10.1038/s44318-023-00013-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 43 2023 1 15 12 14-31 |
| allfieldsSound |
10.1038/s44318-023-00013-0 doi (DE-627)SPR054273986 (SPR)s44318-023-00013-0-e DE-627 ger DE-627 rakwb eng Dong, Yanli verfasserin (orcid)0000-0002-7919-3276 aut Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human $ Na^{+} $/$ Ca^{2+} $ exchanger NCX1.3 in the presence of a specific inhibitor, SEA0400. Conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. We show how regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and predicted to clash with gating helices $ TMs^{1/6} $ at the outward-facing state, thus hindering conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating $ Ca^{2+} $-uptake activity of NCX1.3. Synopsis The exchange of sodium and calcium ions across membranes plays important (patho)physiological roles. Here, cryo-EM is used to study the inhibitor-bound human sodium-calcium exchanger NCX1.3, shedding light on the molecular mechanisms underlying SEA0400- and XIP-mediated inactivation. The XIP region is located within a groove between TMD and CBD2, mediating inactivation by obstructing the conformational transition of gating helices $ TMs^{1/6} $.An SEA0400 molecule is situated within a negatively charged cavity in the transmembrane region, exerting allosteric inhibition by inhibiting the conformational changes of TM2ab.The XIP and SEA0400, though not directly interacting, mutually stabilize each other’s binding pockets in the inward-facing conformation through loopTM1-2, thereby cooperatively inhibiting the $ Ca^{2 +} $-uptake activity of NCX.Allosteric inhibition by SEA0400 is selectively effective in the antiporter’s reverse mode. Cryo-EM data show how two key endogenous and exogenous sodium/calcium ion-exchange inhibitors block conformational rearrangements associated with ion exchange by NCX1.3. Sodium-calcium Exchanger (dpeaa)DE-He213 Calcium Homeostasis (dpeaa)DE-He213 Allosteric Inhibition (dpeaa)DE-He213 SEA0400 (dpeaa)DE-He213 Exchanger Inhibitory Peptide (XIP) (dpeaa)DE-He213 Yu, Zhuoya aut Li, Yue (orcid)0000-0002-1211-7383 aut Huang, Bo aut Bai, Qinru aut Gao, Yiwei (orcid)0000-0001-8169-9332 aut Chen, Qihao aut Li, Na aut He, Lingli aut Zhao, Yan (orcid)0000-0002-4348-256X aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 43(2023), 1 vom: 15. Dez., Seite 14-31 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:43 year:2023 number:1 day:15 month:12 pages:14-31 https://dx.doi.org/10.1038/s44318-023-00013-0 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 43 2023 1 15 12 14-31 |
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English |
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Enthalten in The EMBO Journal 43(2023), 1 vom: 15. Dez., Seite 14-31 volume:43 year:2023 number:1 day:15 month:12 pages:14-31 |
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Enthalten in The EMBO Journal 43(2023), 1 vom: 15. Dez., Seite 14-31 volume:43 year:2023 number:1 day:15 month:12 pages:14-31 |
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Sodium-calcium Exchanger Calcium Homeostasis Allosteric Inhibition SEA0400 Exchanger Inhibitory Peptide (XIP) |
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Dong, Yanli @@aut@@ Yu, Zhuoya @@aut@@ Li, Yue @@aut@@ Huang, Bo @@aut@@ Bai, Qinru @@aut@@ Gao, Yiwei @@aut@@ Chen, Qihao @@aut@@ Li, Na @@aut@@ He, Lingli @@aut@@ Zhao, Yan @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR054273986</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240105064748.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240105s2023 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1038/s44318-023-00013-0</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR054273986</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s44318-023-00013-0-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Dong, Yanli</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-7919-3276</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2023</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2023</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human $ Na^{+} $/$ Ca^{2+} $ exchanger NCX1.3 in the presence of a specific inhibitor, SEA0400. Conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. We show how regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and predicted to clash with gating helices $ TMs^{1/6} $ at the outward-facing state, thus hindering conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating $ Ca^{2+} $-uptake activity of NCX1.3.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis The exchange of sodium and calcium ions across membranes plays important (patho)physiological roles. Here, cryo-EM is used to study the inhibitor-bound human sodium-calcium exchanger NCX1.3, shedding light on the molecular mechanisms underlying SEA0400- and XIP-mediated inactivation. 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|
| author |
Dong, Yanli |
| spellingShingle |
Dong, Yanli misc Sodium-calcium Exchanger misc Calcium Homeostasis misc Allosteric Inhibition misc SEA0400 misc Exchanger Inhibitory Peptide (XIP) Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400 |
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1460-2075 |
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Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400 Sodium-calcium Exchanger (dpeaa)DE-He213 Calcium Homeostasis (dpeaa)DE-He213 Allosteric Inhibition (dpeaa)DE-He213 SEA0400 (dpeaa)DE-He213 Exchanger Inhibitory Peptide (XIP) (dpeaa)DE-He213 |
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misc Sodium-calcium Exchanger misc Calcium Homeostasis misc Allosteric Inhibition misc SEA0400 misc Exchanger Inhibitory Peptide (XIP) |
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misc Sodium-calcium Exchanger misc Calcium Homeostasis misc Allosteric Inhibition misc SEA0400 misc Exchanger Inhibitory Peptide (XIP) |
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Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400 |
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Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400 |
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Dong, Yanli Yu, Zhuoya Li, Yue Huang, Bo Bai, Qinru Gao, Yiwei Chen, Qihao Li, Na He, Lingli Zhao, Yan |
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Elektronische Aufsätze |
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structural insight into the allosteric inhibition of human sodium-calcium exchanger ncx1 by xip and sea0400 |
| title_auth |
Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400 |
| abstract |
Abstract Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human $ Na^{+} $/$ Ca^{2+} $ exchanger NCX1.3 in the presence of a specific inhibitor, SEA0400. Conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. We show how regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and predicted to clash with gating helices $ TMs^{1/6} $ at the outward-facing state, thus hindering conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating $ Ca^{2+} $-uptake activity of NCX1.3. Synopsis The exchange of sodium and calcium ions across membranes plays important (patho)physiological roles. Here, cryo-EM is used to study the inhibitor-bound human sodium-calcium exchanger NCX1.3, shedding light on the molecular mechanisms underlying SEA0400- and XIP-mediated inactivation. The XIP region is located within a groove between TMD and CBD2, mediating inactivation by obstructing the conformational transition of gating helices $ TMs^{1/6} $.An SEA0400 molecule is situated within a negatively charged cavity in the transmembrane region, exerting allosteric inhibition by inhibiting the conformational changes of TM2ab.The XIP and SEA0400, though not directly interacting, mutually stabilize each other’s binding pockets in the inward-facing conformation through loopTM1-2, thereby cooperatively inhibiting the $ Ca^{2 +} $-uptake activity of NCX.Allosteric inhibition by SEA0400 is selectively effective in the antiporter’s reverse mode. Cryo-EM data show how two key endogenous and exogenous sodium/calcium ion-exchange inhibitors block conformational rearrangements associated with ion exchange by NCX1.3. © The Author(s) 2023 |
| abstractGer |
Abstract Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human $ Na^{+} $/$ Ca^{2+} $ exchanger NCX1.3 in the presence of a specific inhibitor, SEA0400. Conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. We show how regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and predicted to clash with gating helices $ TMs^{1/6} $ at the outward-facing state, thus hindering conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating $ Ca^{2+} $-uptake activity of NCX1.3. Synopsis The exchange of sodium and calcium ions across membranes plays important (patho)physiological roles. Here, cryo-EM is used to study the inhibitor-bound human sodium-calcium exchanger NCX1.3, shedding light on the molecular mechanisms underlying SEA0400- and XIP-mediated inactivation. The XIP region is located within a groove between TMD and CBD2, mediating inactivation by obstructing the conformational transition of gating helices $ TMs^{1/6} $.An SEA0400 molecule is situated within a negatively charged cavity in the transmembrane region, exerting allosteric inhibition by inhibiting the conformational changes of TM2ab.The XIP and SEA0400, though not directly interacting, mutually stabilize each other’s binding pockets in the inward-facing conformation through loopTM1-2, thereby cooperatively inhibiting the $ Ca^{2 +} $-uptake activity of NCX.Allosteric inhibition by SEA0400 is selectively effective in the antiporter’s reverse mode. Cryo-EM data show how two key endogenous and exogenous sodium/calcium ion-exchange inhibitors block conformational rearrangements associated with ion exchange by NCX1.3. © The Author(s) 2023 |
| abstract_unstemmed |
Abstract Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human $ Na^{+} $/$ Ca^{2+} $ exchanger NCX1.3 in the presence of a specific inhibitor, SEA0400. Conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. We show how regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and predicted to clash with gating helices $ TMs^{1/6} $ at the outward-facing state, thus hindering conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating $ Ca^{2+} $-uptake activity of NCX1.3. Synopsis The exchange of sodium and calcium ions across membranes plays important (patho)physiological roles. Here, cryo-EM is used to study the inhibitor-bound human sodium-calcium exchanger NCX1.3, shedding light on the molecular mechanisms underlying SEA0400- and XIP-mediated inactivation. The XIP region is located within a groove between TMD and CBD2, mediating inactivation by obstructing the conformational transition of gating helices $ TMs^{1/6} $.An SEA0400 molecule is situated within a negatively charged cavity in the transmembrane region, exerting allosteric inhibition by inhibiting the conformational changes of TM2ab.The XIP and SEA0400, though not directly interacting, mutually stabilize each other’s binding pockets in the inward-facing conformation through loopTM1-2, thereby cooperatively inhibiting the $ Ca^{2 +} $-uptake activity of NCX.Allosteric inhibition by SEA0400 is selectively effective in the antiporter’s reverse mode. Cryo-EM data show how two key endogenous and exogenous sodium/calcium ion-exchange inhibitors block conformational rearrangements associated with ion exchange by NCX1.3. © The Author(s) 2023 |
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Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400 |
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https://dx.doi.org/10.1038/s44318-023-00013-0 |
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Yu, Zhuoya Li, Yue Huang, Bo Bai, Qinru Gao, Yiwei Chen, Qihao Li, Na He, Lingli Zhao, Yan |
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Yu, Zhuoya Li, Yue Huang, Bo Bai, Qinru Gao, Yiwei Chen, Qihao Li, Na He, Lingli Zhao, Yan |
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10.1038/s44318-023-00013-0 |
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| score |
7.398529 |