Effect of intracellular loop 3 on intrinsic dynamics of human $ β_{2} $-adrenergic receptor
Background To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human $ β_{2} $-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazol...
Ausführliche Beschreibung
Autor*in: |
Ozcan, Ozer [verfasserIn] |
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Englisch |
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2013 |
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© Ozcan et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License ( |
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Übergeordnetes Werk: |
Enthalten in: BMC structural biology - London : BioMed Central, 2001, 13(2013), 1 vom: 09. Nov. |
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Übergeordnetes Werk: |
volume:13 ; year:2013 ; number:1 ; day:09 ; month:11 |
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DOI / URN: |
10.1186/1472-6807-13-29 |
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Katalog-ID: |
SPR02862968X |
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520 | |a Background To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human $ β_{2} $-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 μs molecular dynamics (MD) simulation at 310 K. Results After around 600 ns, the loop model started a transition to a “very inactive” conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein’s binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 Å from 11 Å, which was further elaborated by docking studies. Conclusions The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the “very inactive” state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes. | ||
650 | 4 | |a ICL3 |7 (dpeaa)DE-He213 | |
650 | 4 | |a Molecular dynamics simulation |7 (dpeaa)DE-He213 | |
650 | 4 | |a Transmembrane helix 6 |7 (dpeaa)DE-He213 | |
650 | 4 | |a G-protein binding site |7 (dpeaa)DE-He213 | |
650 | 4 | |a Ligand docking |7 (dpeaa)DE-He213 | |
650 | 4 | |a Essential dynamics |7 (dpeaa)DE-He213 | |
700 | 1 | |a Uyar, Arzu |4 aut | |
700 | 1 | |a Doruker, Pemra |4 aut | |
700 | 1 | |a Akten, Ebru Demet |4 aut | |
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10.1186/1472-6807-13-29 doi (DE-627)SPR02862968X (SPR)1472-6807-13-29-e DE-627 ger DE-627 rakwb eng Ozcan, Ozer verfasserin aut Effect of intracellular loop 3 on intrinsic dynamics of human $ β_{2} $-adrenergic receptor 2013 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Ozcan et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License ( Background To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human $ β_{2} $-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 μs molecular dynamics (MD) simulation at 310 K. Results After around 600 ns, the loop model started a transition to a “very inactive” conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein’s binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 Å from 11 Å, which was further elaborated by docking studies. Conclusions The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the “very inactive” state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes. ICL3 (dpeaa)DE-He213 Molecular dynamics simulation (dpeaa)DE-He213 Transmembrane helix 6 (dpeaa)DE-He213 G-protein binding site (dpeaa)DE-He213 Ligand docking (dpeaa)DE-He213 Essential dynamics (dpeaa)DE-He213 Uyar, Arzu aut Doruker, Pemra aut Akten, Ebru Demet aut Enthalten in BMC structural biology London : BioMed Central, 2001 13(2013), 1 vom: 09. Nov. (DE-627)331018810 (DE-600)2050440-8 1472-6807 nnns volume:13 year:2013 number:1 day:09 month:11 https://dx.doi.org/10.1186/1472-6807-13-29 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 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_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 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_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2013 1 09 11 |
spelling |
10.1186/1472-6807-13-29 doi (DE-627)SPR02862968X (SPR)1472-6807-13-29-e DE-627 ger DE-627 rakwb eng Ozcan, Ozer verfasserin aut Effect of intracellular loop 3 on intrinsic dynamics of human $ β_{2} $-adrenergic receptor 2013 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Ozcan et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License ( Background To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human $ β_{2} $-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 μs molecular dynamics (MD) simulation at 310 K. Results After around 600 ns, the loop model started a transition to a “very inactive” conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein’s binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 Å from 11 Å, which was further elaborated by docking studies. Conclusions The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the “very inactive” state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes. ICL3 (dpeaa)DE-He213 Molecular dynamics simulation (dpeaa)DE-He213 Transmembrane helix 6 (dpeaa)DE-He213 G-protein binding site (dpeaa)DE-He213 Ligand docking (dpeaa)DE-He213 Essential dynamics (dpeaa)DE-He213 Uyar, Arzu aut Doruker, Pemra aut Akten, Ebru Demet aut Enthalten in BMC structural biology London : BioMed Central, 2001 13(2013), 1 vom: 09. Nov. (DE-627)331018810 (DE-600)2050440-8 1472-6807 nnns volume:13 year:2013 number:1 day:09 month:11 https://dx.doi.org/10.1186/1472-6807-13-29 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 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_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 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_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2013 1 09 11 |
allfields_unstemmed |
10.1186/1472-6807-13-29 doi (DE-627)SPR02862968X (SPR)1472-6807-13-29-e DE-627 ger DE-627 rakwb eng Ozcan, Ozer verfasserin aut Effect of intracellular loop 3 on intrinsic dynamics of human $ β_{2} $-adrenergic receptor 2013 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Ozcan et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License ( Background To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human $ β_{2} $-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 μs molecular dynamics (MD) simulation at 310 K. Results After around 600 ns, the loop model started a transition to a “very inactive” conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein’s binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 Å from 11 Å, which was further elaborated by docking studies. Conclusions The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the “very inactive” state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes. ICL3 (dpeaa)DE-He213 Molecular dynamics simulation (dpeaa)DE-He213 Transmembrane helix 6 (dpeaa)DE-He213 G-protein binding site (dpeaa)DE-He213 Ligand docking (dpeaa)DE-He213 Essential dynamics (dpeaa)DE-He213 Uyar, Arzu aut Doruker, Pemra aut Akten, Ebru Demet aut Enthalten in BMC structural biology London : BioMed Central, 2001 13(2013), 1 vom: 09. Nov. (DE-627)331018810 (DE-600)2050440-8 1472-6807 nnns volume:13 year:2013 number:1 day:09 month:11 https://dx.doi.org/10.1186/1472-6807-13-29 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 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_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 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_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2013 1 09 11 |
allfieldsGer |
10.1186/1472-6807-13-29 doi (DE-627)SPR02862968X (SPR)1472-6807-13-29-e DE-627 ger DE-627 rakwb eng Ozcan, Ozer verfasserin aut Effect of intracellular loop 3 on intrinsic dynamics of human $ β_{2} $-adrenergic receptor 2013 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Ozcan et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License ( Background To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human $ β_{2} $-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 μs molecular dynamics (MD) simulation at 310 K. Results After around 600 ns, the loop model started a transition to a “very inactive” conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein’s binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 Å from 11 Å, which was further elaborated by docking studies. Conclusions The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the “very inactive” state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes. ICL3 (dpeaa)DE-He213 Molecular dynamics simulation (dpeaa)DE-He213 Transmembrane helix 6 (dpeaa)DE-He213 G-protein binding site (dpeaa)DE-He213 Ligand docking (dpeaa)DE-He213 Essential dynamics (dpeaa)DE-He213 Uyar, Arzu aut Doruker, Pemra aut Akten, Ebru Demet aut Enthalten in BMC structural biology London : BioMed Central, 2001 13(2013), 1 vom: 09. Nov. (DE-627)331018810 (DE-600)2050440-8 1472-6807 nnns volume:13 year:2013 number:1 day:09 month:11 https://dx.doi.org/10.1186/1472-6807-13-29 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 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_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 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_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2013 1 09 11 |
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10.1186/1472-6807-13-29 doi (DE-627)SPR02862968X (SPR)1472-6807-13-29-e DE-627 ger DE-627 rakwb eng Ozcan, Ozer verfasserin aut Effect of intracellular loop 3 on intrinsic dynamics of human $ β_{2} $-adrenergic receptor 2013 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © Ozcan et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License ( Background To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human $ β_{2} $-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 μs molecular dynamics (MD) simulation at 310 K. Results After around 600 ns, the loop model started a transition to a “very inactive” conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein’s binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 Å from 11 Å, which was further elaborated by docking studies. Conclusions The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the “very inactive” state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes. ICL3 (dpeaa)DE-He213 Molecular dynamics simulation (dpeaa)DE-He213 Transmembrane helix 6 (dpeaa)DE-He213 G-protein binding site (dpeaa)DE-He213 Ligand docking (dpeaa)DE-He213 Essential dynamics (dpeaa)DE-He213 Uyar, Arzu aut Doruker, Pemra aut Akten, Ebru Demet aut Enthalten in BMC structural biology London : BioMed Central, 2001 13(2013), 1 vom: 09. Nov. (DE-627)331018810 (DE-600)2050440-8 1472-6807 nnns volume:13 year:2013 number:1 day:09 month:11 https://dx.doi.org/10.1186/1472-6807-13-29 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 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_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 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_4338 GBV_ILN_4367 GBV_ILN_4700 AR 13 2013 1 09 11 |
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Effect of intracellular loop 3 on intrinsic dynamics of human $ β_{2} $-adrenergic receptor |
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title_full |
Effect of intracellular loop 3 on intrinsic dynamics of human $ β_{2} $-adrenergic receptor |
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Ozcan, Ozer |
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BMC structural biology |
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Ozcan, Ozer Uyar, Arzu Doruker, Pemra Akten, Ebru Demet |
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Elektronische Aufsätze |
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Ozcan, Ozer |
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title_sort |
effect of intracellular loop 3 on intrinsic dynamics of human $ β_{2} $-adrenergic receptor |
title_auth |
Effect of intracellular loop 3 on intrinsic dynamics of human $ β_{2} $-adrenergic receptor |
abstract |
Background To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human $ β_{2} $-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 μs molecular dynamics (MD) simulation at 310 K. Results After around 600 ns, the loop model started a transition to a “very inactive” conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein’s binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 Å from 11 Å, which was further elaborated by docking studies. Conclusions The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the “very inactive” state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes. © Ozcan et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License ( |
abstractGer |
Background To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human $ β_{2} $-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 μs molecular dynamics (MD) simulation at 310 K. Results After around 600 ns, the loop model started a transition to a “very inactive” conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein’s binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 Å from 11 Å, which was further elaborated by docking studies. Conclusions The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the “very inactive” state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes. © Ozcan et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License ( |
abstract_unstemmed |
Background To understand the effect of the long intracellular loop 3 (ICL3) on the intrinsic dynamics of human $ β_{2} $-adrenergic receptor, molecular dynamics (MD) simulations were performed on two different models, both of which were based on the inactive crystal structure in complex with carazolol (after removal of carazolol and T4-lysozyme). In the so-called loop model, the ICL3 region that is missing in available crystal structures was modeled as an unstructured loop of 32-residues length, whereas in the clipped model, the two open ends were covalently bonded to each other. The latter model without ICL3 was taken as a reference, which has also been commonly used in recent computational studies. Each model was embedded into POPC bilayer membrane with explicit water and subjected to a 1 μs molecular dynamics (MD) simulation at 310 K. Results After around 600 ns, the loop model started a transition to a “very inactive” conformation, which is characterized by a further movement of the intracellular half of transmembrane helix 6 (TM6) towards the receptor core, and a close packing of ICL3 underneath the membrane completely blocking the G-protein’s binding site. Concurrently, the binding site at the extracellular part of the receptor expanded slightly with the Ser207-Asp113 distance increasing to 18 Å from 11 Å, which was further elaborated by docking studies. Conclusions The essential dynamics analysis indicated a strong coupling between the extracellular and intracellular parts of the intact receptor, implicating a functional relevance for allosteric regulation. In contrast, no such transition to the “very inactive” state, nor any structural correlation, was observed in the clipped model without ICL3. Furthermore, elastic network analysis using different conformers for the loop model indicated a consistent picture on the specific ICL3 conformational change being driven by global modes. © Ozcan et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License ( |
collection_details |
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title_short |
Effect of intracellular loop 3 on intrinsic dynamics of human $ β_{2} $-adrenergic receptor |
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