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Title: Structural basis for selectivity and diversity in angiotensin II receptors

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. 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.

Authors:
 [1];  [2];  [3];  [2];  [2];  [2];  [2];  [4];  [5];  [5];  [6];  [7];  [3];  [8];  [8];  [5];  [5];  [9];  [9];  [4] more »;  [9];  [4];  [5];  [2];  [2];  [2] « less
+ Show Author Affiliations
  1. Univ. of Southern California, Los Angeles, CA (United States); Zhejiang Univ., Zhejiang (China)
  2. Univ. of Southern California, Los Angeles, CA (United States)
  3. SLAC National Accelerator Lab., Menlo Park, CA (United States)
  4. Merck & Co., Inc., Kenilworth, NJ (United States)
  5. Merck & Co., Inc., West Point, PA (United States)
  6. Univ. of Hamburg, Hamburg (Germany); Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)
  7. Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)
  8. Arizona State Univ., Tempe, AZ (United States)
  9. Merck & Co., Inc., North Wales, PA (United States)
Publication Date:
Research Org.:
SLAC National Accelerator Lab. (SLAC), Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1361139
Grant/Contract Number:  
AC02-76SF00515
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 544; Journal Issue: 7650; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

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, and Cherezov, Vadim. Structural basis for selectivity and diversity in angiotensin II receptors. United States: N. p., 2017. Web. doi:10.1038/nature22035.
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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. Structural basis for selectivity and diversity in angiotensin II receptors. United States. https://doi.org/10.1038/nature22035
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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, and Cherezov, Vadim. Thu . "Structural basis for selectivity and diversity in angiotensin II receptors". United States. https://doi.org/10.1038/nature22035. https://www.osti.gov/servlets/purl/1361139.
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@article{osti_1361139,
title = {Structural basis for selectivity and diversity in angiotensin II receptors},
author = {Zhang, Haitao and Han, Gye Won and Batyuk, Alexander and Ishchenko, Andrii and White, Kate L. and Patel, Nilkanth and Sadybekov, Anastasiia and Zamlynny, Beata and Rudd, Michael T. and Hollenstein, Kaspar and Tolstikova, Alexandra and White, Thomas A. and Hunter, Mark S. and Weierstall, Uwe and Liu, Wei and Babaoglu, Kerim and Moore, Eric L. and Katz, Ryan D. and Shipman, Jennifer M. and Garcia-Calvo, Margarita and Sharma, Sujata and Sheth, Payal and Soisson, Stephen M. and Stevens, Raymond C. and Katritch, Vsevolod and Cherezov, Vadim},
abstractNote = {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.},
doi = {10.1038/nature22035},
journal = {Nature (London)},
number = 7650,
volume = 544,
place = {United States},
year = {Thu Apr 20 00:00:00 EDT 2017},
month = {Thu Apr 20 00:00:00 EDT 2017}
}
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    • Cheng, Robert; Abela, Rafael; Hennig, Michael
    • Acta Crystallographica Section A Foundations and Advances, Vol. 74, Issue a1
    • DOI: 10.1107/s0108767318095570

    Sample delivery for serial crystallography at free-electron lasers and synchrotrons
    journal, January 2019

    • Grünbein, Marie Luise; Nass Kovacs, Gabriela
    • Acta Crystallographica Section D Structural Biology, Vol. 75, Issue 2
    • DOI: 10.1107/s205979831801567x

    Anti‐fibrotic mechanisms of angiotensin AT 2 ‐receptor stimulation
    journal, April 2019

    • Sumners, Colin; Peluso, Antonio Augusto; Haugaard, Andreas Houe
    • Acta Physiologica
    • DOI: 10.1111/apha.13280

    Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure
    journal, September 2019

    • Arendse, Lauren B.; Danser, A. H. Jan; Poglitsch, Marko
    • Pharmacological Reviews, Vol. 71, Issue 4
    • DOI: 10.1124/pr.118.017129

    Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs
    journal, October 2019

    • Luginina, Aleksandra; Gusach, Anastasiia; Marin, Egor
    • Science Advances, Vol. 5, Issue 10
    • DOI: 10.1126/sciadv.aax2518

    The renin-angiotensin system: going beyond the classical paradigms
    journal, May 2019

    • Santos, Robson Augusto Souza; Oudit, Gavin Y.; Verano-Braga, Thiago
    • American Journal of Physiology-Heart and Circulatory Physiology, Vol. 316, Issue 5
    • DOI: 10.1152/ajpheart.00723.2018

    Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology
    journal, July 2018

    The Renin-Angiotensin-Aldosterone System as a Therapeutic Target in Late Injury Caused by Ischemia-Reperfusion
    journal, April 2018

    • Rodríguez-Lara, Simón Quetzalcóatl; García-Benavides, Leonel; Miranda-Díaz, Alejandra Guillermina
    • International Journal of Endocrinology, Vol. 2018
    • DOI: 10.1155/2018/3614303

    Angiotensin II Type 2 Receptor and Receptor Mas Are Colocalized and Functionally Interdependent in Obese Zucker Rat Kidney
    journal, October 2017

    Understanding Angiotensin II Type 1 Receptor Signaling in Vascular Pathophysiology
    journal, May 2018

    Better agonist for the opioid receptors
    journal, February 2018

    • Badshah, Syed Lal; Ullah, Asad; Al-showiman, Salim S.
    • Chemistry Central Journal, Vol. 12, Issue 1
    • DOI: 10.1186/s13065-018-0383-8

    The association between angiotensin II type 1 receptor A1166C gene polymorphism and the risk of essential hypertension: a meta-analysis
    journal, September 2019

    • Fajar, Jonny Karunia; Susanti, Melly; Pikir, Budi Susetio
    • Egyptian Journal of Medical Human Genetics, Vol. 20, Issue 1
    • DOI: 10.1186/s43042-019-0016-3

    Short-wavelength free-electron laser sources and science: a review
    text, January 2017

    • Seddon, E. A.; Clarke, J. A.; Dunning, D. J.
    • Deutsches Elektronen-Synchrotron, DESY, Hamburg
    • DOI: 10.3204/pubdb-2018-00596

    Could Mycolactone Inspire New Potent Analgesics? Perspectives and Pitfalls
    journal, September 2019

    • Reynaert, Marie-Line; Dupoiron, Denis; Yeramian, Edouard
    • Toxins, Vol. 11, Issue 9
    • DOI: 10.3390/toxins11090516

    X-ray free electron laser: opportunities for drug discovery
    journal, November 2017

    • Cheng, Robert K. Y.; Abela, Rafael; Hennig, Michael
    • Essays in Biochemistry, Vol. 61, Issue 5
    • DOI: 10.1042/ebc20170031

    Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors
    text, January 2019

    Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs
    text, January 2019

    Short-wavelength free-electron laser sources and science: a review
    journal, October 2017

    • Seddon, E. A.; Clarke, J. A.; Dunning, D. J.
    • Reports on Progress in Physics, Vol. 80, Issue 11
    • DOI: 10.1088/1361-6633/aa7cca

    Angiotensin peptide synthesis and cyclic nucleotide modulation in sympathetic stellate ganglia
    journal, January 2020

    • Bardsley, Emma N.; Neely, Oliver C.; Paterson, David J.
    • Journal of Molecular and Cellular Cardiology, Vol. 138
    • DOI: 10.1016/j.yjmcc.2019.11.157

    Counter-regulatory renin–angiotensin system in cardiovascular disease
    journal, August 2019

    • Paz Ocaranza, Maria; Riquelme, Jaime A.; García, Lorena
    • Nature Reviews Cardiology, Vol. 17, Issue 2
    • DOI: 10.1038/s41569-019-0244-8

    Structural basis of ligand recognition at the human MT1 melatonin receptor
    journal, April 2019

    Deciphering collaborative sidechain motions in proteins during molecular dynamics simulations
    journal, September 2020

    Novel Therapeutic Approaches Targeting the Renin-Angiotensin System and Associated Peptides in Hypertension and Heart Failure
    journal, September 2019

    • Arendse, Lauren B.; Danser, A. H. Jan; Poglitsch, Marko
    • Pharmacological Reviews, Vol. 71, Issue 4
    • DOI: 10.1124/pr.118.017129

    Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs
    journal, October 2019

    • Luginina, Aleksandra; Gusach, Anastasiia; Marin, Egor
    • Science Advances, Vol. 5, Issue 10
    • DOI: 10.1126/sciadv.aax2518

    The Renin-Angiotensin-Aldosterone System as a Therapeutic Target in Late Injury Caused by Ischemia-Reperfusion
    journal, April 2018

    • Rodríguez-Lara, Simón Quetzalcóatl; García-Benavides, Leonel; Miranda-Díaz, Alejandra Guillermina
    • International Journal of Endocrinology, Vol. 2018
    • DOI: 10.1155/2018/3614303

    Better agonist for the opioid receptors
    journal, February 2018

    • Badshah, Syed Lal; Ullah, Asad; Al-showiman, Salim S.
    • Chemistry Central Journal, Vol. 12, Issue 1
    • DOI: 10.1186/s13065-018-0383-8

    In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson’s Disease
    journal, June 2018

    Could Mycolactone Inspire New Potent Analgesics? Perspectives and Pitfalls
    journal, September 2019

    • Reynaert, Marie-Line; Dupoiron, Denis; Yeramian, Edouard
    • Toxins, Vol. 11, Issue 9
    • DOI: 10.3390/toxins11090516

    A Bacterial Toxin with Analgesic Properties: Hyperpolarization of DRG Neurons by Mycolactone
    journal, July 2017

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