Structural insights into ligand recognition and activation of angiotensin receptors

Abstract

G protein-coupled angiotensin II receptors, AT₁R and AT₂R, are integral components of the renin-angiotensin system (RAS) that regulates blood pressure and fluid balance in humans. While AT₁R is a well-established target of angiotensin receptor blockers (ARBs) for managing hypertension and a prime system for studying biased signaling, AT₂R has been recognized as a promising target against neuropathic pain and lung fibrosis. In this review, we discuss how recent structural advances illuminate ligand-binding modes and subtype selectivity, shared and distinct features of the receptors, their transducer-coupling patterns, and downstream signaling responses. We also underscore the key ATR aspects that require further studies to fully appreciate the mechanistic framework that fine-tunes their cellular and physiological functions, providing untapped potential for drug discovery.

Keywords: G protein-coupled receptors; activation mechanism; angiotensin II receptors; biased signaling; ligand; subtype selectivity.