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

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 beta -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.

Automated summary

G protein-coupled receptors (GPCRs) are a critical target for drug development, and the comprehensive characterization of the angiotensin II (AngII) type 1 receptor (AT1R) provides insights into designing allosteric GPCR modulators.