Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design

Shaoyong Lu (), Xinheng He, Zhao Yang, Zongtao Chai, Shuhua Zhou, Junyan Wang, Ashfaq Ur Rehman, Duan Ni, Jun Pu, Jinpeng Sun () and Jian Zhang ()
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Shaoyong Lu: Ningxia Medical University
Xinheng He: Chinese Academy of Sciences
Zhao Yang: School of Medicine, Shandong University
Zongtao Chai: Eastern Hepatobiliary Surgery Hospital, Second Military Medical University
Shuhua Zhou: School of Medicine, Shandong University
Junyan Wang: School of Medicine, Shandong University
Ashfaq Ur Rehman: Shanghai Jiao Tong University, School of Medicine
Duan Ni: Shanghai Jiao Tong University, School of Medicine
Jun Pu: Renji Hospital, Shanghai Jiao Tong University, School of Medicine
Jinpeng Sun: School of Medicine, Shandong University
Jian Zhang: Ningxia Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract G protein-coupled receptors (GPCRs) are the most common proteins targeted by approved drugs. A complete mechanistic elucidation of large-scale conformational transitions underlying the activation mechanisms of GPCRs is of critical importance for therapeutic drug development. Here, we apply a combined computational and experimental framework integrating extensive molecular dynamics simulations, Markov state models, site-directed mutagenesis, and conformational biosensors to investigate the conformational landscape of the angiotensin II (AngII) type 1 receptor (AT1 receptor) — a prototypical class A GPCR—activation. Our findings suggest a synergistic transition mechanism for AT1 receptor activation. A key intermediate state is identified in the activation pathway, which possesses a cryptic binding site within the intracellular region of the receptor. Mutation of this cryptic site prevents activation of the downstream G protein signaling and β-arrestin-mediated pathways by the endogenous AngII octapeptide agonist, suggesting an allosteric regulatory mechanism. Together, these findings provide a deeper understanding of AT1 receptor activation at an atomic level and suggest avenues for the design of allosteric AT1 receptor modulators with a broad range of applications in GPCR biology, biophysics, and medicinal chemistry.

Date: 2021
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DOI: 10.1038/s41467-021-25020-9

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