Delineating the conformational landscape and intrinsic properties of the angiotensin II type 2 receptor using a computational study.

As a key regulator for the renin-angiotensin system, a class A G protein-coupled receptor (GPCR), AngII type 2 receptor (ATR), plays a pivotal role in the homeostasis of the cardiovascular system. Compared with other GPCRs, ATR has a unique antagonist-bound conformation and its mechanism is still an enigma. Here, we applied combined dynamic and evolutional approaches to investigate the conformational space and intrinsic properties of ATR. With molecular dynamic simulations, Markov State Models, and statistics coupled analysis, we captured the conformational landscape of ATR and identified its uniquity from both dynamical and evolutional viewpoints. A cryptic pocket was also discovered in the intermediate state during conformation transitions. These findings offer a deeper understanding of the ATR mechanism at an atomic level and provide hints for the design of novel ATR modulators.