Author
Listed:
- Haitao Zhang
(Bridge Institute, University of Southern California
Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University)
- Gye Won Han
(Bridge Institute, University of Southern California)
- Alexander Batyuk
(Linac Coherent Light Source, SLAC National Accelerator Laboratory)
- Andrii Ishchenko
(Bridge Institute, University of Southern California)
- Kate L. White
(Bridge Institute, University of Southern California
Bridge Institute, University of Southern California)
- Nilkanth Patel
(Bridge Institute, University of Southern California)
- Anastasiia Sadybekov
(Bridge Institute, University of Southern California)
- Beata Zamlynny
(MRL, Merck & Co., Inc.)
- Michael T. Rudd
(MRL, Merck & Co., Inc.)
- Kaspar Hollenstein
(MRL, Merck & Co., Inc.)
- Alexandra Tolstikova
(Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestraße 85, 22607 Hamburg, Germany
University of Hamburg)
- Thomas A. White
(Center for Free Electron Laser Science, Deutsches Elektronen-Synchrotron DESY, Notkestraße 85, 22607 Hamburg, Germany)
- Mark S. Hunter
(Linac Coherent Light Source, SLAC National Accelerator Laboratory)
- Uwe Weierstall
(Arizona State University)
- Wei Liu
(School of Molecular Sciences and Biodesign Center for Applied Structural Discovery, Biodesign Institute, Arizona State University)
- Kerim Babaoglu
(MRL, Merck & Co., Inc.)
- Eric L. Moore
(MRL, Merck & Co., Inc.)
- Ryan D. Katz
(MRL, Merck & Co., Inc.)
- Jennifer M. Shipman
(MRL, Merck & Co., Inc.)
- Margarita Garcia-Calvo
(MRL, Merck & Co., Inc.)
- Sujata Sharma
(MRL, Merck & Co., Inc.)
- Payal Sheth
(MRL, Merck & Co., Inc.)
- Stephen M. Soisson
(MRL, Merck & Co., Inc.)
- Raymond C. Stevens
(Bridge Institute, University of Southern California
Bridge Institute, University of Southern California)
- Vsevolod Katritch
(Bridge Institute, University of Southern California
Bridge Institute, University of Southern California)
- Vadim Cherezov
(Bridge Institute, University of Southern California)
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.
Suggested Citation
Haitao Zhang & Gye Won Han & Alexander Batyuk & Andrii Ishchenko & Kate L. White & Nilkanth Patel & Anastasiia Sadybekov & Beata Zamlynny & Michael T. Rudd & Kaspar Hollenstein & Alexandra Tolstikova , 2017.
"Structural basis for selectivity and diversity in angiotensin II receptors,"
Nature, Nature, vol. 544(7650), pages 327-332, April.
Handle:
RePEc:nat:nature:v:544:y:2017:i:7650:d:10.1038_nature22035
DOI: 10.1038/nature22035
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