Angiotensin II type 1 receptor (AT<inf>1</inf>R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT<inf>1</inf>R blockers (ARBs), the structural basis for AT<inf>1</inf>R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high-quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT<inf>1</inf>R in complex with its selective antagonist ZD7155 at 2.9-Å resolution. The AT<inf>1</inf>R-ZD7155 complex structure revealed key structural features of AT<inf>1</inf>R and critical interactions for ZD7155 binding. Docking simulations of the clinically used ARBs into the AT<inf>1</inf>R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT<inf>1</inf>R structure-function relationship and structure-based drug design. Structure determination of human Angiotensin II type 1 receptor bound to an antagonist using serial femtosecond crystallography with X-ray free-electron laser and docking studies of other common anti-hypertensive drugs into the structure offer insights into design of blood pressure modulators.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)