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Elife. 2019 Dec 19;8. pii: e50279. doi: 10.7554/eLife.50279.

Common activation mechanism of class A GPCRs.

Zhou Q#1, Yang D#2,3,4, Wu M1,3,5, Guo Y1,3,5, Guo W2,3,4, Zhong L2,3,4, Cai X2,4, Dai A2,4, Jang W6, Shakhnovich EI7, Liu ZJ1,5, Stevens RC1,5, Lambert NA6, Babu MM8, Wang MW2,3,4,5,9, Zhao S1,5.

Author information

1
iHuman Institute, ShanghaiTech University, Shanghai, China.
2
The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
3
University of Chinese Academy of Sciences, Beijing, China.
4
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
5
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
6
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, United States.
7
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States.
8
MRC Laboratory of Molecular Biology, Cambridge, United Kingdom.
9
School of Pharmacy, Fudan University, Shanghai, China.
#
Contributed equally

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.

KEYWORDS:

GPCR; activation mechanism; allostery; computational biology; drug discovery; genetic diseases; human; molecular biophysics; signal transduction; structural biology; systems biology

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