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Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design
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Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design
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Journal Article
Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design
2021
Overview
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 (AT
1
receptor) — a prototypical class A GPCR—activation. Our findings suggest a synergistic transition mechanism for AT
1
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 AT
1
receptor activation at an atomic level and suggest avenues for the design of allosteric AT
1
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/95
/ 14/5
/ 96/35
/ Arrestin
/ Design
/ Humanities and Social Sciences
/ Humans
/ Molecular Dynamics Simulation
/ Mutation
/ Proteins
/ Receptor, Angiotensin, Type 1 - chemistry
/ Receptor, Angiotensin, Type 1 - genetics
/ Receptor, Angiotensin, Type 1 - metabolism
/ Regulatory mechanisms (biology)
/ Science
