Structural basis for selectivity and diversity in angiotensin II receptors

Zhang, Haitao; Han, Gye Won; Batyuk, Alexander; Ishchenko, Andrii; White, Kate L.; Patel, Nilkanth; Sadybekov, Anastasiia; Zamlynny, Beata; Rudd, Michael T.; Hollenstein, Kaspar; Tolstikova, Alexandra; White, Thomas A.; Hunter, Mark S.; Weierstall, Uwe; Liu, Wei; Babaoglu, Kerim; Moore, Eric L.; Katz, Ryan D.; Shipman, Jennifer M.; Garcia-Calvo, Margarita; Sharma, Sujata; Sheth, Payal; Soisson, Stephen M.; Stevens, Raymond C.; Katritch, Vsevolod; Cherezov, Vadim

doi:10.1038/nature22035

Structural basis for selectivity and diversity in angiotensin II receptors

Journal Article · Thu Apr 20 00:00:00 EDT 2017 · Nature (London)

DOI:https://doi.org/10.1038/nature22035· OSTI ID:1361139

Zhang, Haitao ^[1]; Han, Gye Won ^[2]; Batyuk, Alexander ^[3]; Ishchenko, Andrii ^[2]; White, Kate L. ^[2]; Patel, Nilkanth ^[2]; Sadybekov, Anastasiia ^[2]; Zamlynny, Beata ^[4]; Rudd, Michael T. ^[5]; Hollenstein, Kaspar ^[5]; Tolstikova, Alexandra ^[6]; White, Thomas A. ^[7]; Hunter, Mark S. ^[3]; Weierstall, Uwe ^[8]; Liu, Wei ^[8]; Babaoglu, Kerim ^[5]; Moore, Eric L. ^[5]; Katz, Ryan D. ^[9]; Shipman, Jennifer M. ^[9]; Garcia-Calvo, Margarita ^[4] more »

Univ. of Southern California, Los Angeles, CA (United States); Zhejiang Univ., Zhejiang (China)
Univ. of Southern California, Los Angeles, CA (United States)
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Merck & Co., Inc., Kenilworth, NJ (United States)
Merck & Co., Inc., West Point, PA (United States)
Univ. of Hamburg, Hamburg (Germany); Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)
Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)
Arizona State Univ., Tempe, AZ (United States)
Merck & Co., Inc., North Wales, PA (United States)

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. Finally, 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.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Lab. (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1361139

Alternate ID(s):: OSTI ID: 1368259

Journal Information:: Nature (London), Journal Name: Nature (London) Journal Issue: 7650 Vol. 544; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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New approaches towards the understanding of integral membrane proteins: A structural perspective on G protein-coupled receptors: Structural Perspective on G Protein-Coupled Receptors Grisshammer, Reinhard Protein Science, Vol. 26, Issue 8 https://doi.org/10.1002/pro.3200	journal	June 2017
Structures of Non-rhodopsin GPCRs Elucidated Through X-Ray Crystallography Nasrallah, Chady; Lebon, Guillaume Structure and Function of GPCRs https://doi.org/10.1007/7355_2017_28	book	January 2017
A benchmark study of loop modeling methods applied to G protein-coupled receptors Wink, Lee H.; Baker, Daniel L.; Cole, Judith A. Journal of Computer-Aided Molecular Design, Vol. 33, Issue 6 https://doi.org/10.1007/s10822-019-00196-x	journal	May 2019
Brain Renin–Angiotensin System Blockade Attenuates Methamphetamine-Induced Hyperlocomotion and Neurotoxicity Jiang, Linhong; Zhu, Ruiming; Bu, Qian Neurotherapeutics, Vol. 15, Issue 2 https://doi.org/10.1007/s13311-018-0613-8	journal	February 2018
Biased signalling: from simple switches to allosteric microprocessors Smith, Jeffrey S.; Lefkowitz, Robert J.; Rajagopal, Sudarshan Nature Reviews Drug Discovery, Vol. 17, Issue 4 https://doi.org/10.1038/nrd.2017.229	journal	January 2018
Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors Gusach, Anastasiia; Luginina, Aleksandra; Marin, Egor Nature Communications, Vol. 10, Issue 1 https://doi.org/10.1038/s41467-019-13348-2	journal	December 2019
Crystal structure of the endogenous agonist-bound prostanoid receptor EP3 Morimoto, Kazushi; Suno, Ryoji; Hotta, Yunhong Nature Chemical Biology, Vol. 15, Issue 1 https://doi.org/10.1038/s41589-018-0171-8	journal	December 2018
Orthosteric and allosteric action of the C5a receptor antagonists Liu, Heng; Kim, Hee Ryung; Deepak, R. N. V. Krishna Nature Structural & Molecular Biology, Vol. 25, Issue 6 https://doi.org/10.1038/s41594-018-0067-z	journal	June 2018
Structural basis for signal recognition and transduction by platelet-activating-factor receptor Cao, Can; Tan, Qiuxiang; Xu, Chanjuan Nature Structural & Molecular Biology, Vol. 25, Issue 6 https://doi.org/10.1038/s41594-018-0068-y	journal	May 2018
Crystal structure of the human angiotensin II type 2 receptor bound to an angiotensin II analog Asada, Hidetsugu; Horita, Shoichiro; Hirata, Kunio Nature Structural & Molecular Biology, Vol. 25, Issue 7 https://doi.org/10.1038/s41594-018-0079-8	journal	July 2018
Use multiscale simulation to explore the effects of the homodimerizations between different conformation states on the activation and allosteric pathway for the μ-opioid receptor Zhang, Xi; Yuan, Yuan; Wang, Longrong Physical Chemistry Chemical Physics, Vol. 20, Issue 19 https://doi.org/10.1039/c8cp02016g	journal	January 2018
The effect of dimerization on the activation and conformational dynamics of adenosine A ₁ receptor Li, Yang; Wang, Mukuo; Gao, Na Physical Chemistry Chemical Physics, Vol. 21, Issue 41 https://doi.org/10.1039/c9cp04060a	journal	January 2019
X-ray free electron laser: opportunities for drug discovery Cheng, Robert K. Y.; Abela, Rafael; Hennig, Michael Essays in Biochemistry, Vol. 61, Issue 5 https://doi.org/10.1042/ebc20170031	journal	November 2017
Advances in understanding the role of angiotensin-regulated proteins in kidney diseases Sanz, Ana Belén; Ramos, Adrian Mario; Soler, Maria Jose Expert Review of Proteomics, Vol. 16, Issue 1 https://doi.org/10.1080/14789450.2018.1545577	journal	November 2018
An outlook on using serial femtosecond crystallography in drug discovery Mishin, Alexey; Gusach, Anastasiia; Luginina, Aleksandra Expert Opinion on Drug Discovery, Vol. 14, Issue 9 https://doi.org/10.1080/17460441.2019.1626822	journal	May 2019
Short-wavelength free-electron laser sources and science: a review Seddon, E. A.; Clarke, J. A.; Dunning, D. J. Reports on Progress in Physics, Vol. 80, Issue 11 https://doi.org/10.1088/1361-6633/aa7cca	journal	October 2017
X-ray free-electron laser: opportunities for drug discovery Cheng, Robert; Abela, Rafael; Hennig, Michael Acta Crystallographica Section A Foundations and Advances, Vol. 74, Issue a1 https://doi.org/10.1107/s0108767318095570	journal	July 2018
Sample delivery for serial crystallography at free-electron lasers and synchrotrons Grünbein, Marie Luise; Nass Kovacs, Gabriela Acta Crystallographica Section D Structural Biology, Vol. 75, Issue 2 https://doi.org/10.1107/s205979831801567x	journal	January 2019
Anti‐fibrotic mechanisms of angiotensin AT ₂ ‐receptor stimulation Sumners, Colin; Peluso, Antonio Augusto; Haugaard, Andreas Houe Acta Physiologica https://doi.org/10.1111/apha.13280	journal	April 2019
The renin-angiotensin system: going beyond the classical paradigms Santos, Robson Augusto Souza; Oudit, Gavin Y.; Verano-Braga, Thiago American Journal of Physiology-Heart and Circulatory Physiology, Vol. 316, Issue 5 https://doi.org/10.1152/ajpheart.00723.2018	journal	May 2019
Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology Forrester, Steven J.; Booz, George W.; Sigmund, Curt D. Physiological Reviews, Vol. 98, Issue 3 https://doi.org/10.1152/physrev.00038.2017	journal	July 2018
Angiotensin II Type 2 Receptor and Receptor Mas Are Colocalized and Functionally Interdependent in Obese Zucker Rat Kidney Patel, Sanket N.; Ali, Quaisar; Samuel, Preethi Hypertension, Vol. 70, Issue 4 https://doi.org/10.1161/hypertensionaha.117.09679	journal	October 2017
Understanding Angiotensin II Type 1 Receptor Signaling in Vascular Pathophysiology Eguchi, Satoru; Kawai, Tatsuo; Scalia, Rosario Hypertension, Vol. 71, Issue 5 https://doi.org/10.1161/hypertensionaha.118.10266	journal	May 2018
The association between angiotensin II type 1 receptor A1166C gene polymorphism and the risk of essential hypertension: a meta-analysis Fajar, Jonny Karunia; Susanti, Melly; Pikir, Budi Susetio Egyptian Journal of Medical Human Genetics, Vol. 20, Issue 1 https://doi.org/10.1186/s43042-019-0016-3	journal	September 2019
Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors Gusach, Anastasiia; Luginina, Aleksandra; Marin, Egor RWTH Aachen University https://doi.org/10.18154/rwth-2020-00731	text	January 2019
Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs Luginina, Aleksandra; Gusach, Anastasiia; Marin, Egor RWTH Aachen University https://doi.org/10.18154/rwth-2020-02115	text	January 2019
Short-wavelength free-electron laser sources and science: a review Seddon, E. A.; Clarke, J. A.; Dunning, D. J. Deutsches Elektronen-Synchrotron, DESY, Hamburg https://doi.org/10.3204/pubdb-2018-00596	text	January 2017

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