1. Computational and Systems Biology
  2. Structural Biology and Molecular Biophysics
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Common activation mechanism of class A GPCRs

  1. Qingtong Zhou
  2. Dehua Yang
  3. Meng Wu
  4. Yu Guo
  5. Wangjing Guo
  6. Li Zhong
  7. Xiaoqing Cai
  8. Antao Dai
  9. Wonjo Jang
  10. Eugene I Shakhnovich
  11. Zhi-Jie Liu
  12. Raymond C Stevens
  13. Nevin A Lambert
  14. M Madan Babu  Is a corresponding author
  15. Ming-Wei Wang  Is a corresponding author
  16. Suwen Zhao  Is a corresponding author
  1. ShanghaiTech University, China
  2. Shanghai Institute of Materia Medica, China
  3. Augusta University, United States
  4. Harvard University, United States
  5. MRC Laboratory of Molecular Biology, United Kingdom
Research Article
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Cite this article as: eLife 2019;8:e50279 doi: 10.7554/eLife.50279

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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 6 and 7.

Article and author information

Author details

  1. Qingtong Zhou

    iHuman Institute, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Dehua Yang

    The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3028-3243
  3. Meng Wu

    iHuman Institute, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yu Guo

    iHuman Institute, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Wangjing Guo

    The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Li Zhong

    The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Xiaoqing Cai

    The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Antao Dai

    The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Wonjo Jang

    Department of Pharmacology and Toxicology, Augusta University, Augusta, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Eugene I Shakhnovich

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4769-2265
  11. Zhi-Jie Liu

    iHuman Institute, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7279-2893
  12. Raymond C Stevens

    iHuman Institute, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Nevin A Lambert

    Department of Pharmacology and Toxicology, Augusta University, Augusta, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. M Madan Babu

    MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    For correspondence
    madanm@mrc-lmb.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  15. Ming-Wei Wang

    The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai, China
    For correspondence
    mwwang@simm.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
  16. Suwen Zhao

    iHuman Institute, ShanghaiTech University, Shanghai, China
    For correspondence
    zhaosw@shanghaitech.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5609-434X

Funding

Medical Research Council (MC_U105185859)

  • M Madan Babu

National Mega R&D Program for Drug Discovery (2018ZX09735-001)

  • Ming-Wei Wang

National Key R&D Program of China (2016YFC0905900)

  • Suwen Zhao

National Key R&D Program of China (2018YFA0507000)

  • Suwen Zhao

National Key R&D Program of China (2018YFA0507000)

  • Ming-Wei Wang

National Natural Science Foundation of China (31971178)

  • Suwen Zhao

National Natural Science Foundation of China (81872915)

  • Ming-Wei Wang

Novo Nordisk-CAS Research (NNCAS-2017-1-CC)

  • Dehua Yang

Young Talent Program of Shanghai

  • Suwen Zhao

Shanghai Science and Technology Development Fund (16ZR1448500)

  • Suwen Zhao

Shanghai Science and Technology Development Fund (16ZR1407100)

  • Antao Dai

National Natural Science Foundation of China (21704064)

  • Qingtong Zhou

National Natural Science Foundation of China (81573479)

  • Dehua Yang

National Natural Science Foundation of China (81773792)

  • Dehua Yang

National Mega R&D Program for Drug Discovery (2018ZX09711002-002-005)

  • Dehua Yang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Yibing Shan, DE Shaw Research, United States

Publication history

  1. Received: July 17, 2019
  2. Accepted: December 19, 2019
  3. Accepted Manuscript published: December 19, 2019 (version 1)
  4. Version of Record published: January 10, 2020 (version 2)
  5. Version of Record updated: February 25, 2020 (version 3)

Copyright

© 2019, Zhou et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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