Faculty Collaboration Database

Structural basis for selectivity and diversity in angiotensin II receptors. Nature 2017 Apr 20;544(7650):327-332

Date

04/06/2017

Pubmed ID

28379944

Pubmed Central ID

PMC5525545

DOI

10.1038/nature22035

Scopus ID

2-s2.0-85017413904 (requires institutional sign-in at Scopus site)   185 Citations

Abstract

The angiotensin II receptors AT₁R and AT₂R serve as key components of the renin-angiotensin-aldosterone system. AT₁R has a central role in the regulation of blood pressure, but the function of AT₂R is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human AT₂R bound to an AT₂R-selective ligand and to an AT₁R/AT₂R dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or β-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure-activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.

Author List

Zhang H, Han GW, Batyuk A, Ishchenko A, White KL, Patel N, Sadybekov A, Zamlynny B, Rudd MT, Hollenstein K, Tolstikova A, White TA, Hunter MS, Weierstall U, Liu W, Babaoglu K, Moore EL, Katz RD, Shipman JM, Garcia-Calvo M, Sharma S, Sheth P, Soisson SM, Stevens RC, Katritch V, Cherezov V

Author

Wei Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiotensin II Type 2 Receptor Blockers
Binding Sites
Crystallography, X-Ray
Drug Design
Heterotrimeric GTP-Binding Proteins
Humans
Ligands
Models, Molecular
Molecular Docking Simulation
Mutation
Protein Binding
Protein Conformation
Receptor, Angiotensin, Type 1
Receptor, Angiotensin, Type 2
Signal Transduction
Structure-Activity Relationship
Substrate Specificity
beta-Arrestins