Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of AT₁R Initiated by van der Waals Attraction

We present a succession of structural changes involved in hormone peptide activation of a prototypical GPCR. Microsecond molecular dynamics simulation generated conformational ensembles reveal propagation of structural changes through key "microswitches" within human AT₁R bound to native hormone. The endocrine octa-peptide angiotensin II (AngII) activates AT₁R signaling in our bodies which maintains physiological blood pressure, electrolyte balance, and cardiovascular homeostasis. Excessive AT₁R activation is associated with pathogenesis of hypertension and cardiovascular diseases which are treated by sartan drugs. The mechanism of AT₁R inhibition by sartans has been elucidated by 2.8 Å X-ray structures, mutagenesis, and computational analyses. Yet, the mechanism of AT₁R activation by AngII is unclear. The current study delineates an activation scheme initiated by AngII binding. A van der Waals "grasp" interaction between Phe8^AngII with Ile288^7.39 in AT₁R induced mechanical strain pulling Tyr292^7.43 and breakage of critical interhelical H-bonds, first between Tyr292^7.43 and Val108^3.32 and second between Asn111^3.35 and Asn295^7.46. Subsequently changes are observed in conserved microswitches DRY^TM3, Yx7K(R)^TM5, CWxP^TM6, and NPxxY^TM7 in AT₁R. Activating the microswitches in the intracellular region of AT₁R may trigger formation of the G-protein binding pocket as well as exposure of helix-8 to cytoplasm. Thus, the active-like conformation of AT₁R is initiated by the van der Waals interaction of Phe8^AngII with Ile288^7.39, followed by systematic reorganization of critical interhelical H-bonds and activation of microswitches.