Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of AT(1)R 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 AT(1)R bound to native hormone. The endocrine octa-peptide angiotensin II (AngII) activates AT(1)R signaling in our bodies which maintains physiological blood pressure, electrolyte balance, and cardiovascular homeostasis. Excessive AT(1)R activation is associated with pathogenesis of hypertension and cardiovascular diseases which are treated by sartan drugs. The mechanism of AT(1)R inhibition by sartans has been elucidated by 2.8 angstrom X-ray structures, mutagenesis, and computational analyses. Yet, the mechanism of AT(1)R 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 AT(1)R 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 DRYTM3, Yx7K(R)(TMS), CWxP(TM6), and NPxxY(TM7) in AT(1)R Activating the microswitches in the intracellular region of AT(1)R may trigger formation of the G-protein binding pocket as well as exposure of helix-8 to cytoplasm. Thus, the active-like conformation of AT(1)R 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.