Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of ATR 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 ATR bound to native hormone. The endocrine octa-peptide angiotensin II (AngII) activates ATR signaling in our bodies which maintains physiological blood pressure, electrolyte balance, and cardiovascular homeostasis. Excessive ATR activation is associated with pathogenesis of hypertension and cardiovascular diseases which are treated by sartan drugs. The mechanism of ATR inhibition by sartans has been elucidated by 2.8 Å X-ray structures, mutagenesis, and computational analyses. Yet, the mechanism of ATR activation by AngII is unclear. The current study delineates an activation scheme initiated by AngII binding. A van der Waals "grasp" interaction between Phe8 with Ile288 in ATR induced mechanical strain pulling Tyr292 and breakage of critical interhelical H-bonds, first between Tyr292 and Val108 and second between Asn111 and Asn295. Subsequently changes are observed in conserved microswitches DRY, Yx7K(R), CWxP, and NPxxY in ATR. Activating the microswitches in the intracellular region of ATR may trigger formation of the G-protein binding pocket as well as exposure of helix-8 to cytoplasm. Thus, the active-like conformation of ATR is initiated by the van der Waals interaction of Phe8 with Ile288, followed by systematic reorganization of critical interhelical H-bonds and activation of microswitches.