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

By X. He, Z. Yang, Z. Chai, J. Wang, A. Rehman, D. Ni, J. Pu, J. Sun, J. Zhang, S. Lu. 2021

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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. G protein-coupled receptors (GPCRs) are a critical target in modern drug development across a wide range of indications. Here the authors provide a comprehensive characterization of a typical GPCR, the angiotensin II (AngII) type 1 receptor (AT1R), and provide insight into its activation mechanism that suggest avenues for the design of allosteric GPCR modulators.

Subfields: Cellular and Molecular Neuroscience, Computational Theory and Mathematics, Molecular Biology