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dc.contributor.authorZhou, Qingtong
dc.contributor.authorYang, Dehua
dc.contributor.authorWu, Meng
dc.contributor.authorGuo, Yu
dc.contributor.authorGuo, Wanjing
dc.contributor.authorZhong, Li
dc.contributor.authorCai, Xiaoqing
dc.contributor.authorDai, Antao
dc.contributor.authorJang, Wonjo
dc.contributor.authorShakhnovich, Eugene I
dc.contributor.authorLiu, Zhi-Jie
dc.contributor.authorStevens, Raymond C
dc.contributor.authorLambert, Nevin A
dc.contributor.authorBabu, M Madan
dc.contributor.authorWang, Ming-Wei
dc.contributor.authorZhao, Suwen
dc.date.accessioned2020-01-11T05:15:10Z
dc.date.available2020-01-11T05:15:10Z
dc.date.issued2019-12-19
dc.date.submitted2019-07-17
dc.identifier.issn2050-084X
dc.identifier.other50279
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/300785
dc.descriptionFunder: Young Talent Program of Shanghai
dc.description.abstractClass 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.
dc.languageen
dc.publishereLife Sciences Publications, Ltd
dc.rightsAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectResearch Article
dc.subjectComputational and Systems Biology
dc.subjectStructural Biology and Molecular Biophysics
dc.subjectallostery
dc.subjectGPCR
dc.subjectactivation mechanism
dc.subjectgenetic diseases
dc.subjectsignal transduction
dc.subjectdrug discovery
dc.subjectHuman
dc.titleCommon activation mechanism of class A GPCRs.
dc.typeArticle
dc.date.updated2020-01-11T05:15:08Z
prism.publicationNameElife
dc.identifier.doi10.17863/CAM.47859
dcterms.dateAccepted2019-12-19
rioxxterms.versionofrecord10.7554/eLife.50279
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
datacite.contributor.supervisoreditor: Shan, Yibing
datacite.contributor.supervisorsenior_editor: Boudker, Olga
dc.contributor.orcidZhou, Qingtong [0000-0001-8124-3079]
dc.contributor.orcidYang, Dehua [0000-0003-3028-3243]
dc.contributor.orcidShakhnovich, Eugene I [0000-0002-4769-2265]
dc.contributor.orcidLiu, Zhi-Jie [0000-0001-7279-2893]
dc.contributor.orcidLambert, Nevin A [0000-0001-7550-0921]
dc.contributor.orcidZhao, Suwen [0000-0001-5609-434X]
dc.identifier.eissn2050-084X
pubs.funder-project-idMedical Research Council (MC_U105185859)
pubs.funder-project-idNovo Nordisk-CAS Research (NNCAS-2017-1-CC)
pubs.funder-project-idShanghai Science and Technology Development Fund (16ZR1448500)
pubs.funder-project-idShanghai Science and Technology Development Fund (16ZR1407100)
pubs.funder-project-idNational Natural Science Foundation of China (21704064)
pubs.funder-project-idNational Natural Science Foundation of China (81573479)
pubs.funder-project-idNational Natural Science Foundation of China (81773792)
pubs.funder-project-idNational Natural Science Foundation of China (31971178)
pubs.funder-project-idNational Mega R&D Program for Drug Discovery (2018ZX09735-001)
pubs.funder-project-idNational Key R&D Program of China (2016YFC0905900)
pubs.funder-project-idNational Mega R&D Program for Drug Discovery (2018ZX09711002-002-005)
pubs.funder-project-idNational Key R&D Program of China (2018YFA0507000)
pubs.funder-project-idNational Natural Science Foundation of China (81872915)
pubs.funder-project-idNational Institute of General Medical Sciences (GM130142)
cam.issuedOnline2019-12-19


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)