Common activation mechanism of class A GPCRs

Class A G-protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third of all marketed drugs target members of this family. GPCR activation is an allosteric pro...
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Autor*in:	Qingtong Zhou [verfasserIn] Dehua Yang [verfasserIn] Meng Wu [verfasserIn] Yu Guo [verfasserIn] Wanjing Guo [verfasserIn] Li Zhong [verfasserIn] Xiaoqing Cai [verfasserIn] Antao Dai [verfasserIn] Wonjo Jang [verfasserIn] Eugene I Shakhnovich [verfasserIn] Zhi-Jie Liu [verfasserIn] Raymond C Stevens [verfasserIn] Nevin A Lambert [verfasserIn] M Madan Babu [verfasserIn] Ming-Wei Wang [verfasserIn] Suwen Zhao [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Schlagwörter:	allostery GPCR activation mechanism genetic diseases signal transduction drug discovery

Übergeordnetes Werk:	In: eLife - eLife Sciences Publications Ltd, 2013, 8(2019)
Übergeordnetes Werk:	volume:8 ; year:2019

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.7554/eLife.50279

Katalog-ID:	DOAJ00444132X

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allfields	10.7554/eLife.50279 doi (DE-627)DOAJ00444132X (DE-599)DOAJ1fd7d071b55047e5a53a68b7fcb67b21 DE-627 ger DE-627 rakwb eng QH301-705.5 Qingtong Zhou verfasserin aut Common activation mechanism of class A GPCRs 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Class A G-protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third of all marketed drugs target members of this family. GPCR activation is an allosteric process that couples agonist binding to G-protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue level changes of this movement remain less well understood. Here, we report a framework to quantify conformational changes. By analyzing the conformational changes in 234 structures from 45 class A GPCRs, we discovered a common GPCR activation pathway comprising of 34 residue pairs and 35 residues. The pathway unifies previous findings into a common activation mechanism and strings together the scattered key motifs such as CWxP, DRY, Na+ pocket, NPxxY and PIF, thereby directly linking the bottom of ligand-binding pocket with G-protein coupling region. Site-directed mutagenesis experiments support this proposition and reveal that rational mutations of residues in this pathway can be used to obtain receptors that are constitutively active or inactive. The common activation pathway provides the mechanistic interpretation of constitutively activating, inactivating and disease mutations. As a module responsible for activation, the common pathway allows for decoupling of the evolution of the ligand binding site and G-protein-binding region. Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature. allostery GPCR activation mechanism genetic diseases signal transduction drug discovery Medicine R Science Q Biology (General) Dehua Yang verfasserin aut Meng Wu verfasserin aut Yu Guo verfasserin aut Wanjing Guo verfasserin aut Li Zhong verfasserin aut Xiaoqing Cai verfasserin aut Antao Dai verfasserin aut Wonjo Jang verfasserin aut Eugene I Shakhnovich verfasserin aut Zhi-Jie Liu verfasserin aut Raymond C Stevens verfasserin aut Nevin A Lambert verfasserin aut M Madan Babu verfasserin aut Ming-Wei Wang verfasserin aut Suwen Zhao verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 8(2019) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:8 year:2019 https://doi.org/10.7554/eLife.50279 kostenfrei https://doaj.org/article/1fd7d071b55047e5a53a68b7fcb67b21 kostenfrei https://elifesciences.org/articles/50279 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 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_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2019
spelling	10.7554/eLife.50279 doi (DE-627)DOAJ00444132X (DE-599)DOAJ1fd7d071b55047e5a53a68b7fcb67b21 DE-627 ger DE-627 rakwb eng QH301-705.5 Qingtong Zhou verfasserin aut Common activation mechanism of class A GPCRs 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Class A G-protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third of all marketed drugs target members of this family. GPCR activation is an allosteric process that couples agonist binding to G-protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue level changes of this movement remain less well understood. Here, we report a framework to quantify conformational changes. By analyzing the conformational changes in 234 structures from 45 class A GPCRs, we discovered a common GPCR activation pathway comprising of 34 residue pairs and 35 residues. The pathway unifies previous findings into a common activation mechanism and strings together the scattered key motifs such as CWxP, DRY, Na+ pocket, NPxxY and PIF, thereby directly linking the bottom of ligand-binding pocket with G-protein coupling region. Site-directed mutagenesis experiments support this proposition and reveal that rational mutations of residues in this pathway can be used to obtain receptors that are constitutively active or inactive. The common activation pathway provides the mechanistic interpretation of constitutively activating, inactivating and disease mutations. As a module responsible for activation, the common pathway allows for decoupling of the evolution of the ligand binding site and G-protein-binding region. Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature. allostery GPCR activation mechanism genetic diseases signal transduction drug discovery Medicine R Science Q Biology (General) Dehua Yang verfasserin aut Meng Wu verfasserin aut Yu Guo verfasserin aut Wanjing Guo verfasserin aut Li Zhong verfasserin aut Xiaoqing Cai verfasserin aut Antao Dai verfasserin aut Wonjo Jang verfasserin aut Eugene I Shakhnovich verfasserin aut Zhi-Jie Liu verfasserin aut Raymond C Stevens verfasserin aut Nevin A Lambert verfasserin aut M Madan Babu verfasserin aut Ming-Wei Wang verfasserin aut Suwen Zhao verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 8(2019) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:8 year:2019 https://doi.org/10.7554/eLife.50279 kostenfrei https://doaj.org/article/1fd7d071b55047e5a53a68b7fcb67b21 kostenfrei https://elifesciences.org/articles/50279 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 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_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2019
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allfieldsGer	10.7554/eLife.50279 doi (DE-627)DOAJ00444132X (DE-599)DOAJ1fd7d071b55047e5a53a68b7fcb67b21 DE-627 ger DE-627 rakwb eng QH301-705.5 Qingtong Zhou verfasserin aut Common activation mechanism of class A GPCRs 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Class A G-protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third of all marketed drugs target members of this family. GPCR activation is an allosteric process that couples agonist binding to G-protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue level changes of this movement remain less well understood. Here, we report a framework to quantify conformational changes. By analyzing the conformational changes in 234 structures from 45 class A GPCRs, we discovered a common GPCR activation pathway comprising of 34 residue pairs and 35 residues. The pathway unifies previous findings into a common activation mechanism and strings together the scattered key motifs such as CWxP, DRY, Na+ pocket, NPxxY and PIF, thereby directly linking the bottom of ligand-binding pocket with G-protein coupling region. Site-directed mutagenesis experiments support this proposition and reveal that rational mutations of residues in this pathway can be used to obtain receptors that are constitutively active or inactive. The common activation pathway provides the mechanistic interpretation of constitutively activating, inactivating and disease mutations. As a module responsible for activation, the common pathway allows for decoupling of the evolution of the ligand binding site and G-protein-binding region. Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature. allostery GPCR activation mechanism genetic diseases signal transduction drug discovery Medicine R Science Q Biology (General) Dehua Yang verfasserin aut Meng Wu verfasserin aut Yu Guo verfasserin aut Wanjing Guo verfasserin aut Li Zhong verfasserin aut Xiaoqing Cai verfasserin aut Antao Dai verfasserin aut Wonjo Jang verfasserin aut Eugene I Shakhnovich verfasserin aut Zhi-Jie Liu verfasserin aut Raymond C Stevens verfasserin aut Nevin A Lambert verfasserin aut M Madan Babu verfasserin aut Ming-Wei Wang verfasserin aut Suwen Zhao verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 8(2019) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:8 year:2019 https://doi.org/10.7554/eLife.50279 kostenfrei https://doaj.org/article/1fd7d071b55047e5a53a68b7fcb67b21 kostenfrei https://elifesciences.org/articles/50279 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 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_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2019
allfieldsSound	10.7554/eLife.50279 doi (DE-627)DOAJ00444132X (DE-599)DOAJ1fd7d071b55047e5a53a68b7fcb67b21 DE-627 ger DE-627 rakwb eng QH301-705.5 Qingtong Zhou verfasserin aut Common activation mechanism of class A GPCRs 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Class A G-protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third of all marketed drugs target members of this family. GPCR activation is an allosteric process that couples agonist binding to G-protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue level changes of this movement remain less well understood. Here, we report a framework to quantify conformational changes. By analyzing the conformational changes in 234 structures from 45 class A GPCRs, we discovered a common GPCR activation pathway comprising of 34 residue pairs and 35 residues. The pathway unifies previous findings into a common activation mechanism and strings together the scattered key motifs such as CWxP, DRY, Na+ pocket, NPxxY and PIF, thereby directly linking the bottom of ligand-binding pocket with G-protein coupling region. Site-directed mutagenesis experiments support this proposition and reveal that rational mutations of residues in this pathway can be used to obtain receptors that are constitutively active or inactive. The common activation pathway provides the mechanistic interpretation of constitutively activating, inactivating and disease mutations. As a module responsible for activation, the common pathway allows for decoupling of the evolution of the ligand binding site and G-protein-binding region. Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature. allostery GPCR activation mechanism genetic diseases signal transduction drug discovery Medicine R Science Q Biology (General) Dehua Yang verfasserin aut Meng Wu verfasserin aut Yu Guo verfasserin aut Wanjing Guo verfasserin aut Li Zhong verfasserin aut Xiaoqing Cai verfasserin aut Antao Dai verfasserin aut Wonjo Jang verfasserin aut Eugene I Shakhnovich verfasserin aut Zhi-Jie Liu verfasserin aut Raymond C Stevens verfasserin aut Nevin A Lambert verfasserin aut M Madan Babu verfasserin aut Ming-Wei Wang verfasserin aut Suwen Zhao verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 8(2019) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:8 year:2019 https://doi.org/10.7554/eLife.50279 kostenfrei https://doaj.org/article/1fd7d071b55047e5a53a68b7fcb67b21 kostenfrei https://elifesciences.org/articles/50279 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 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_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 8 2019
language	English
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publishDateDaySort_date	2019-01-01T00:00:00Z
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title	Common activation mechanism of class A GPCRs
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title_auth	Common activation mechanism of class A GPCRs
abstract	Class A G-protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third of all marketed drugs target members of this family. GPCR activation is an allosteric process that couples agonist binding to G-protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue level changes of this movement remain less well understood. Here, we report a framework to quantify conformational changes. By analyzing the conformational changes in 234 structures from 45 class A GPCRs, we discovered a common GPCR activation pathway comprising of 34 residue pairs and 35 residues. The pathway unifies previous findings into a common activation mechanism and strings together the scattered key motifs such as CWxP, DRY, Na+ pocket, NPxxY and PIF, thereby directly linking the bottom of ligand-binding pocket with G-protein coupling region. Site-directed mutagenesis experiments support this proposition and reveal that rational mutations of residues in this pathway can be used to obtain receptors that are constitutively active or inactive. The common activation pathway provides the mechanistic interpretation of constitutively activating, inactivating and disease mutations. As a module responsible for activation, the common pathway allows for decoupling of the evolution of the ligand binding site and G-protein-binding region. Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature.
abstractGer	Class A G-protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third of all marketed drugs target members of this family. GPCR activation is an allosteric process that couples agonist binding to G-protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue level changes of this movement remain less well understood. Here, we report a framework to quantify conformational changes. By analyzing the conformational changes in 234 structures from 45 class A GPCRs, we discovered a common GPCR activation pathway comprising of 34 residue pairs and 35 residues. The pathway unifies previous findings into a common activation mechanism and strings together the scattered key motifs such as CWxP, DRY, Na+ pocket, NPxxY and PIF, thereby directly linking the bottom of ligand-binding pocket with G-protein coupling region. Site-directed mutagenesis experiments support this proposition and reveal that rational mutations of residues in this pathway can be used to obtain receptors that are constitutively active or inactive. The common activation pathway provides the mechanistic interpretation of constitutively activating, inactivating and disease mutations. As a module responsible for activation, the common pathway allows for decoupling of the evolution of the ligand binding site and G-protein-binding region. Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature.
abstract_unstemmed	Class A G-protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third of all marketed drugs target members of this family. GPCR activation is an allosteric process that couples agonist binding to G-protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue level changes of this movement remain less well understood. Here, we report a framework to quantify conformational changes. By analyzing the conformational changes in 234 structures from 45 class A GPCRs, we discovered a common GPCR activation pathway comprising of 34 residue pairs and 35 residues. The pathway unifies previous findings into a common activation mechanism and strings together the scattered key motifs such as CWxP, DRY, Na+ pocket, NPxxY and PIF, thereby directly linking the bottom of ligand-binding pocket with G-protein coupling region. Site-directed mutagenesis experiments support this proposition and reveal that rational mutations of residues in this pathway can be used to obtain receptors that are constitutively active or inactive. The common activation pathway provides the mechanistic interpretation of constitutively activating, inactivating and disease mutations. As a module responsible for activation, the common pathway allows for decoupling of the evolution of the ligand binding site and G-protein-binding region. Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature.
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title_short	Common activation mechanism of class A GPCRs
url	https://doi.org/10.7554/eLife.50279 https://doaj.org/article/1fd7d071b55047e5a53a68b7fcb67b21 https://elifesciences.org/articles/50279 https://doaj.org/toc/2050-084X
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Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third of all marketed drugs target members of this family. GPCR activation is an allosteric process that couples agonist binding to G-protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue level changes of this movement remain less well understood. Here, we report a framework to quantify conformational changes. By analyzing the conformational changes in 234 structures from 45 class A GPCRs, we discovered a common GPCR activation pathway comprising of 34 residue pairs and 35 residues. The pathway unifies previous findings into a common activation mechanism and strings together the scattered key motifs such as CWxP, DRY, Na+ pocket, NPxxY and PIF, thereby directly linking the bottom of ligand-binding pocket with G-protein coupling region. Site-directed mutagenesis experiments support this proposition and reveal that rational mutations of residues in this pathway can be used to obtain receptors that are constitutively active or inactive. The common activation pathway provides the mechanistic interpretation of constitutively activating, inactivating and disease mutations. As a module responsible for activation, the common pathway allows for decoupling of the evolution of the ligand binding site and G-protein-binding region. 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Common activation mechanism of class A GPCRs

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