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Nature. 2017 Apr 20;544(7650):327-332. doi: 10.1038/nature22035. Epub 2017 Apr 5.

Structural basis for selectivity and diversity in angiotensin II receptors.

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Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
Linac Coherent Light Source, SLAC National Accelerator Laboratory, 2575 Sand Hill Road, Menlo Park, California 94025, USA.
Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
MRL, Merck &Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
MRL, Merck &Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, USA.
Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestraße 85, 22607 Hamburg, Germany.
Department of Physics, University of Hamburg, Luruper Chaussee 149, 22761 Hamburg, Germany.
Department of Physics, Arizona State University, Tempe, Arizona 85287, USA.
School of Molecular Sciences and Biodesign Center for Applied Structural Discovery, Biodesign Institute, Arizona State University, Tempe, Arizona 85287, USA.
MRL, Merck &Co., Inc., 503 Louise Lane, North Wales, Pennsylvania 19454, USA.


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.

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