Structural basis for selectivity and diversity in angiotensin II receptors

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, Thomas A. White, Mark S. Hunter, Uwe Weierstall, Wei Liu, Kerim Babaoglu, Eric L. Moore, Ryan D. Katz, Jennifer M. Shipman, Margarita Garcia-Calvo, Sujata Sharma, Payal Sheth, Stephen M. Soisson, Raymond C. Stevens, Vsevolod Katritch () and Vadim Cherezov ()
Additional contact information
Haitao Zhang: Bridge Institute, University of Southern California
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
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
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
Vsevolod Katritch: Bridge Institute, University of Southern California
Vadim Cherezov: Bridge Institute, University of Southern California

Nature, 2017, vol. 544, issue 7650, 327-332

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22035

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