Common activation mechanism of class A GPCRs

By Qingtong Zhou, Dehua Yang, Meng Wu, Yu Guo, Wangjing Guo, Li Zhong, Xiao-qing Cai, A. Dai, Wonjo Jang, Eugene I. Shakhnovich and 6 more. 2019

453 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

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Xinheng He
Chongzhao You
H. Jiang
Dehua Yang
Yi Jiang
H. Xu
Xi Cheng
Qingtong Zhou

Citations in the corpus

Multi-State Modeling of G-protein Coupled Receptors at Experimental Accuracy (2021, neutral): “G-protein coupled receptors (GPCRs) comprise one of the largest protein families in the human genome.9 They are involved in various biological roles such as behavior regulation and regulation of immune system activity.1,2,10,11 They are subdivided into several classes according to sequence homology ”
G protein-coupled receptors: structure- and function-based drug discovery (2021, background): “5b–f).(99,103) The binding of diverse agonists triggers the rotameric switch of W, a highly conserved residue in the “CWxP” motif, and the concomitant side chain rotation of F (Fig.”
AlphaFold2 versus experimental structures: evaluation on G protein-coupled receptors (2022, background): “From this site, ligands could induce receptor conformational changes and alter the functional states of GPCRs [22, 28, 29].”