Common activation mechanism of class A GPCRs
- ShanghaiTech University, China
- Shanghai Institute of Materia Medica, China
- Augusta University, United States
- Harvard University, United States
- MRC Laboratory of Molecular Biology, United Kingdom
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
Eugene I Shakhnovich
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.
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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Common activation mechanism of class A GPCRs
eLife 8:e50279.
https://doi.org/10.7554/eLife.50279
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