Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2

Chronic neuropathic pain is the most complex and challenging clinical problem of a population that sets a major physical and economic burden at the global level. Ca2+-permeable channels functionally orchestrate the processing of pain signals. Among them, N-type voltage-gated calcium channels (VGCC)...
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Gespeichert in:

Autor*in:	Sameera [verfasserIn] Fawad Ali Shah [verfasserIn] Sajid Rashid [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	Chronic neuropathic pain N-type voltage-gated calcium channel (Cav2.2) Non-peptide ω-conotoxin mimetics inhibitor Synaptic transmission

Übergeordnetes Werk:	In: Computational and Structural Biotechnology Journal - Elsevier, 2013, 18(2020), Seite 2357-2372
Übergeordnetes Werk:	volume:18 ; year:2020 ; pages:2357-2372

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1016/j.csbj.2020.08.027

Katalog-ID:	DOAJ054919703

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allfields	10.1016/j.csbj.2020.08.027 doi (DE-627)DOAJ054919703 (DE-599)DOAJ11561b78a9574d41ac479a0b4229f501 DE-627 ger DE-627 rakwb eng TP248.13-248.65 Sameera verfasserin aut Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Chronic neuropathic pain is the most complex and challenging clinical problem of a population that sets a major physical and economic burden at the global level. Ca2+-permeable channels functionally orchestrate the processing of pain signals. Among them, N-type voltage-gated calcium channels (VGCC) hold prominent contribution in the pain signal transduction and serve as prime targets for synaptic transmission block and attenuation of neuropathic pain. Here, we present detailed in silico analysis to comprehend the underlying conformational changes upon Ca2+ ion passage through Cav2.2 to differentially correlate subtle transitions induced via binding of a conopeptide-mimetic alkylphenyl ether-based analogue MVIIA. Interestingly, pronounced conformational changes were witnessed at the proximal carboxyl-terminus of Cav2.2 that attained an upright orientation upon Ca+2 ion permeability. Moreover, remarkable changes were observed in the architecture of channel tunnel. These findings illustrate that inhibitor binding to Cav2.2 may induce more narrowing in the pore size as compared to Ca2+ binding through modulating the hydrophilicity pattern at the selectivity region. A significant reduction in the tunnel volume at the selectivity filter and its enhancement at the activation gate of Ca+2-bound Cav2.2 suggests that ion binding modulates the outward splaying of pore-lining S6 helices to open the voltage gate. Overall, current study delineates dynamic conformational ensembles in terms of Ca+2 ion and MVIIA-associated structural implications in the Cav2.2 that may help in better therapeutic intervention to chronic and neuropathic pain management. Chronic neuropathic pain N-type voltage-gated calcium channel (Cav2.2) Non-peptide ω-conotoxin mimetics inhibitor Synaptic transmission Biotechnology Fawad Ali Shah verfasserin aut Sajid Rashid verfasserin aut In Computational and Structural Biotechnology Journal Elsevier, 2013 18(2020), Seite 2357-2372 (DE-627)731890086 (DE-600)2694435-2 20010370 nnns volume:18 year:2020 pages:2357-2372 https://doi.org/10.1016/j.csbj.2020.08.027 kostenfrei https://doaj.org/article/11561b78a9574d41ac479a0b4229f501 kostenfrei http://www.sciencedirect.com/science/article/pii/S2001037020303809 kostenfrei https://doaj.org/toc/2001-0370 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 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 18 2020 2357-2372
spelling	10.1016/j.csbj.2020.08.027 doi (DE-627)DOAJ054919703 (DE-599)DOAJ11561b78a9574d41ac479a0b4229f501 DE-627 ger DE-627 rakwb eng TP248.13-248.65 Sameera verfasserin aut Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Chronic neuropathic pain is the most complex and challenging clinical problem of a population that sets a major physical and economic burden at the global level. Ca2+-permeable channels functionally orchestrate the processing of pain signals. Among them, N-type voltage-gated calcium channels (VGCC) hold prominent contribution in the pain signal transduction and serve as prime targets for synaptic transmission block and attenuation of neuropathic pain. Here, we present detailed in silico analysis to comprehend the underlying conformational changes upon Ca2+ ion passage through Cav2.2 to differentially correlate subtle transitions induced via binding of a conopeptide-mimetic alkylphenyl ether-based analogue MVIIA. Interestingly, pronounced conformational changes were witnessed at the proximal carboxyl-terminus of Cav2.2 that attained an upright orientation upon Ca+2 ion permeability. Moreover, remarkable changes were observed in the architecture of channel tunnel. These findings illustrate that inhibitor binding to Cav2.2 may induce more narrowing in the pore size as compared to Ca2+ binding through modulating the hydrophilicity pattern at the selectivity region. A significant reduction in the tunnel volume at the selectivity filter and its enhancement at the activation gate of Ca+2-bound Cav2.2 suggests that ion binding modulates the outward splaying of pore-lining S6 helices to open the voltage gate. Overall, current study delineates dynamic conformational ensembles in terms of Ca+2 ion and MVIIA-associated structural implications in the Cav2.2 that may help in better therapeutic intervention to chronic and neuropathic pain management. Chronic neuropathic pain N-type voltage-gated calcium channel (Cav2.2) Non-peptide ω-conotoxin mimetics inhibitor Synaptic transmission Biotechnology Fawad Ali Shah verfasserin aut Sajid Rashid verfasserin aut In Computational and Structural Biotechnology Journal Elsevier, 2013 18(2020), Seite 2357-2372 (DE-627)731890086 (DE-600)2694435-2 20010370 nnns volume:18 year:2020 pages:2357-2372 https://doi.org/10.1016/j.csbj.2020.08.027 kostenfrei https://doaj.org/article/11561b78a9574d41ac479a0b4229f501 kostenfrei http://www.sciencedirect.com/science/article/pii/S2001037020303809 kostenfrei https://doaj.org/toc/2001-0370 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 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 18 2020 2357-2372
allfields_unstemmed	10.1016/j.csbj.2020.08.027 doi (DE-627)DOAJ054919703 (DE-599)DOAJ11561b78a9574d41ac479a0b4229f501 DE-627 ger DE-627 rakwb eng TP248.13-248.65 Sameera verfasserin aut Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Chronic neuropathic pain is the most complex and challenging clinical problem of a population that sets a major physical and economic burden at the global level. Ca2+-permeable channels functionally orchestrate the processing of pain signals. Among them, N-type voltage-gated calcium channels (VGCC) hold prominent contribution in the pain signal transduction and serve as prime targets for synaptic transmission block and attenuation of neuropathic pain. Here, we present detailed in silico analysis to comprehend the underlying conformational changes upon Ca2+ ion passage through Cav2.2 to differentially correlate subtle transitions induced via binding of a conopeptide-mimetic alkylphenyl ether-based analogue MVIIA. Interestingly, pronounced conformational changes were witnessed at the proximal carboxyl-terminus of Cav2.2 that attained an upright orientation upon Ca+2 ion permeability. Moreover, remarkable changes were observed in the architecture of channel tunnel. These findings illustrate that inhibitor binding to Cav2.2 may induce more narrowing in the pore size as compared to Ca2+ binding through modulating the hydrophilicity pattern at the selectivity region. A significant reduction in the tunnel volume at the selectivity filter and its enhancement at the activation gate of Ca+2-bound Cav2.2 suggests that ion binding modulates the outward splaying of pore-lining S6 helices to open the voltage gate. Overall, current study delineates dynamic conformational ensembles in terms of Ca+2 ion and MVIIA-associated structural implications in the Cav2.2 that may help in better therapeutic intervention to chronic and neuropathic pain management. Chronic neuropathic pain N-type voltage-gated calcium channel (Cav2.2) Non-peptide ω-conotoxin mimetics inhibitor Synaptic transmission Biotechnology Fawad Ali Shah verfasserin aut Sajid Rashid verfasserin aut In Computational and Structural Biotechnology Journal Elsevier, 2013 18(2020), Seite 2357-2372 (DE-627)731890086 (DE-600)2694435-2 20010370 nnns volume:18 year:2020 pages:2357-2372 https://doi.org/10.1016/j.csbj.2020.08.027 kostenfrei https://doaj.org/article/11561b78a9574d41ac479a0b4229f501 kostenfrei http://www.sciencedirect.com/science/article/pii/S2001037020303809 kostenfrei https://doaj.org/toc/2001-0370 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 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 18 2020 2357-2372
allfieldsGer	10.1016/j.csbj.2020.08.027 doi (DE-627)DOAJ054919703 (DE-599)DOAJ11561b78a9574d41ac479a0b4229f501 DE-627 ger DE-627 rakwb eng TP248.13-248.65 Sameera verfasserin aut Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Chronic neuropathic pain is the most complex and challenging clinical problem of a population that sets a major physical and economic burden at the global level. Ca2+-permeable channels functionally orchestrate the processing of pain signals. Among them, N-type voltage-gated calcium channels (VGCC) hold prominent contribution in the pain signal transduction and serve as prime targets for synaptic transmission block and attenuation of neuropathic pain. Here, we present detailed in silico analysis to comprehend the underlying conformational changes upon Ca2+ ion passage through Cav2.2 to differentially correlate subtle transitions induced via binding of a conopeptide-mimetic alkylphenyl ether-based analogue MVIIA. Interestingly, pronounced conformational changes were witnessed at the proximal carboxyl-terminus of Cav2.2 that attained an upright orientation upon Ca+2 ion permeability. Moreover, remarkable changes were observed in the architecture of channel tunnel. These findings illustrate that inhibitor binding to Cav2.2 may induce more narrowing in the pore size as compared to Ca2+ binding through modulating the hydrophilicity pattern at the selectivity region. A significant reduction in the tunnel volume at the selectivity filter and its enhancement at the activation gate of Ca+2-bound Cav2.2 suggests that ion binding modulates the outward splaying of pore-lining S6 helices to open the voltage gate. Overall, current study delineates dynamic conformational ensembles in terms of Ca+2 ion and MVIIA-associated structural implications in the Cav2.2 that may help in better therapeutic intervention to chronic and neuropathic pain management. Chronic neuropathic pain N-type voltage-gated calcium channel (Cav2.2) Non-peptide ω-conotoxin mimetics inhibitor Synaptic transmission Biotechnology Fawad Ali Shah verfasserin aut Sajid Rashid verfasserin aut In Computational and Structural Biotechnology Journal Elsevier, 2013 18(2020), Seite 2357-2372 (DE-627)731890086 (DE-600)2694435-2 20010370 nnns volume:18 year:2020 pages:2357-2372 https://doi.org/10.1016/j.csbj.2020.08.027 kostenfrei https://doaj.org/article/11561b78a9574d41ac479a0b4229f501 kostenfrei http://www.sciencedirect.com/science/article/pii/S2001037020303809 kostenfrei https://doaj.org/toc/2001-0370 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 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 18 2020 2357-2372
allfieldsSound	10.1016/j.csbj.2020.08.027 doi (DE-627)DOAJ054919703 (DE-599)DOAJ11561b78a9574d41ac479a0b4229f501 DE-627 ger DE-627 rakwb eng TP248.13-248.65 Sameera verfasserin aut Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Chronic neuropathic pain is the most complex and challenging clinical problem of a population that sets a major physical and economic burden at the global level. Ca2+-permeable channels functionally orchestrate the processing of pain signals. Among them, N-type voltage-gated calcium channels (VGCC) hold prominent contribution in the pain signal transduction and serve as prime targets for synaptic transmission block and attenuation of neuropathic pain. Here, we present detailed in silico analysis to comprehend the underlying conformational changes upon Ca2+ ion passage through Cav2.2 to differentially correlate subtle transitions induced via binding of a conopeptide-mimetic alkylphenyl ether-based analogue MVIIA. Interestingly, pronounced conformational changes were witnessed at the proximal carboxyl-terminus of Cav2.2 that attained an upright orientation upon Ca+2 ion permeability. Moreover, remarkable changes were observed in the architecture of channel tunnel. These findings illustrate that inhibitor binding to Cav2.2 may induce more narrowing in the pore size as compared to Ca2+ binding through modulating the hydrophilicity pattern at the selectivity region. A significant reduction in the tunnel volume at the selectivity filter and its enhancement at the activation gate of Ca+2-bound Cav2.2 suggests that ion binding modulates the outward splaying of pore-lining S6 helices to open the voltage gate. Overall, current study delineates dynamic conformational ensembles in terms of Ca+2 ion and MVIIA-associated structural implications in the Cav2.2 that may help in better therapeutic intervention to chronic and neuropathic pain management. Chronic neuropathic pain N-type voltage-gated calcium channel (Cav2.2) Non-peptide ω-conotoxin mimetics inhibitor Synaptic transmission Biotechnology Fawad Ali Shah verfasserin aut Sajid Rashid verfasserin aut In Computational and Structural Biotechnology Journal Elsevier, 2013 18(2020), Seite 2357-2372 (DE-627)731890086 (DE-600)2694435-2 20010370 nnns volume:18 year:2020 pages:2357-2372 https://doi.org/10.1016/j.csbj.2020.08.027 kostenfrei https://doaj.org/article/11561b78a9574d41ac479a0b4229f501 kostenfrei http://www.sciencedirect.com/science/article/pii/S2001037020303809 kostenfrei https://doaj.org/toc/2001-0370 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 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 18 2020 2357-2372
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callnumber-first	T - Technology
author	Sameera
spellingShingle	Sameera misc TP248.13-248.65 misc Chronic neuropathic pain misc N-type voltage-gated calcium channel (Cav2.2) misc Non-peptide ω-conotoxin mimetics inhibitor misc Synaptic transmission misc Biotechnology Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2
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topic_title	TP248.13-248.65 Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2 Chronic neuropathic pain N-type voltage-gated calcium channel (Cav2.2) Non-peptide ω-conotoxin mimetics inhibitor Synaptic transmission
topic	misc TP248.13-248.65 misc Chronic neuropathic pain misc N-type voltage-gated calcium channel (Cav2.2) misc Non-peptide ω-conotoxin mimetics inhibitor misc Synaptic transmission misc Biotechnology
topic_unstemmed	misc TP248.13-248.65 misc Chronic neuropathic pain misc N-type voltage-gated calcium channel (Cav2.2) misc Non-peptide ω-conotoxin mimetics inhibitor misc Synaptic transmission misc Biotechnology
topic_browse	misc TP248.13-248.65 misc Chronic neuropathic pain misc N-type voltage-gated calcium channel (Cav2.2) misc Non-peptide ω-conotoxin mimetics inhibitor misc Synaptic transmission misc Biotechnology
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title	Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2
ctrlnum	(DE-627)DOAJ054919703 (DE-599)DOAJ11561b78a9574d41ac479a0b4229f501
title_full	Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2
author_sort	Sameera
journal	Computational and Structural Biotechnology Journal
journalStr	Computational and Structural Biotechnology Journal
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author_browse	Sameera Fawad Ali Shah Sajid Rashid
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format_se	Elektronische Aufsätze
author-letter	Sameera
doi_str_mv	10.1016/j.csbj.2020.08.027
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title_sort	conformational ensembles of non-peptide ω-conotoxin mimetics and ca+2 ion binding to human voltage-gated n-type calcium channel cav2.2
callnumber	TP248.13-248.65
title_auth	Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2
abstract	Chronic neuropathic pain is the most complex and challenging clinical problem of a population that sets a major physical and economic burden at the global level. Ca2+-permeable channels functionally orchestrate the processing of pain signals. Among them, N-type voltage-gated calcium channels (VGCC) hold prominent contribution in the pain signal transduction and serve as prime targets for synaptic transmission block and attenuation of neuropathic pain. Here, we present detailed in silico analysis to comprehend the underlying conformational changes upon Ca2+ ion passage through Cav2.2 to differentially correlate subtle transitions induced via binding of a conopeptide-mimetic alkylphenyl ether-based analogue MVIIA. Interestingly, pronounced conformational changes were witnessed at the proximal carboxyl-terminus of Cav2.2 that attained an upright orientation upon Ca+2 ion permeability. Moreover, remarkable changes were observed in the architecture of channel tunnel. These findings illustrate that inhibitor binding to Cav2.2 may induce more narrowing in the pore size as compared to Ca2+ binding through modulating the hydrophilicity pattern at the selectivity region. A significant reduction in the tunnel volume at the selectivity filter and its enhancement at the activation gate of Ca+2-bound Cav2.2 suggests that ion binding modulates the outward splaying of pore-lining S6 helices to open the voltage gate. Overall, current study delineates dynamic conformational ensembles in terms of Ca+2 ion and MVIIA-associated structural implications in the Cav2.2 that may help in better therapeutic intervention to chronic and neuropathic pain management.
abstractGer	Chronic neuropathic pain is the most complex and challenging clinical problem of a population that sets a major physical and economic burden at the global level. Ca2+-permeable channels functionally orchestrate the processing of pain signals. Among them, N-type voltage-gated calcium channels (VGCC) hold prominent contribution in the pain signal transduction and serve as prime targets for synaptic transmission block and attenuation of neuropathic pain. Here, we present detailed in silico analysis to comprehend the underlying conformational changes upon Ca2+ ion passage through Cav2.2 to differentially correlate subtle transitions induced via binding of a conopeptide-mimetic alkylphenyl ether-based analogue MVIIA. Interestingly, pronounced conformational changes were witnessed at the proximal carboxyl-terminus of Cav2.2 that attained an upright orientation upon Ca+2 ion permeability. Moreover, remarkable changes were observed in the architecture of channel tunnel. These findings illustrate that inhibitor binding to Cav2.2 may induce more narrowing in the pore size as compared to Ca2+ binding through modulating the hydrophilicity pattern at the selectivity region. A significant reduction in the tunnel volume at the selectivity filter and its enhancement at the activation gate of Ca+2-bound Cav2.2 suggests that ion binding modulates the outward splaying of pore-lining S6 helices to open the voltage gate. Overall, current study delineates dynamic conformational ensembles in terms of Ca+2 ion and MVIIA-associated structural implications in the Cav2.2 that may help in better therapeutic intervention to chronic and neuropathic pain management.
abstract_unstemmed	Chronic neuropathic pain is the most complex and challenging clinical problem of a population that sets a major physical and economic burden at the global level. Ca2+-permeable channels functionally orchestrate the processing of pain signals. Among them, N-type voltage-gated calcium channels (VGCC) hold prominent contribution in the pain signal transduction and serve as prime targets for synaptic transmission block and attenuation of neuropathic pain. Here, we present detailed in silico analysis to comprehend the underlying conformational changes upon Ca2+ ion passage through Cav2.2 to differentially correlate subtle transitions induced via binding of a conopeptide-mimetic alkylphenyl ether-based analogue MVIIA. Interestingly, pronounced conformational changes were witnessed at the proximal carboxyl-terminus of Cav2.2 that attained an upright orientation upon Ca+2 ion permeability. Moreover, remarkable changes were observed in the architecture of channel tunnel. These findings illustrate that inhibitor binding to Cav2.2 may induce more narrowing in the pore size as compared to Ca2+ binding through modulating the hydrophilicity pattern at the selectivity region. A significant reduction in the tunnel volume at the selectivity filter and its enhancement at the activation gate of Ca+2-bound Cav2.2 suggests that ion binding modulates the outward splaying of pore-lining S6 helices to open the voltage gate. Overall, current study delineates dynamic conformational ensembles in terms of Ca+2 ion and MVIIA-associated structural implications in the Cav2.2 that may help in better therapeutic intervention to chronic and neuropathic pain management.
collection_details	GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 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
title_short	Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2
url	https://doi.org/10.1016/j.csbj.2020.08.027 https://doaj.org/article/11561b78a9574d41ac479a0b4229f501 http://www.sciencedirect.com/science/article/pii/S2001037020303809 https://doaj.org/toc/2001-0370
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author2	Fawad Ali Shah Sajid Rashid
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doi_str	10.1016/j.csbj.2020.08.027
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up_date	2024-07-04T01:07:08.580Z
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Conformational ensembles of non-peptide ω-conotoxin mimetics and Ca+2 ion binding to human voltage-gated N-type calcium channel Cav2.2

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