IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v544y2017i7650d10.1038_nature22035.html
   My bibliography  Save this article

Structural basis for selectivity and diversity in angiotensin II receptors

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature22035
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.

    File URL: https://libkey.io/10.1038/nature22035?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Jinkang Shen & Dongqi Zhang & Yao Fu & Anqi Chen & Xiaoli Yang & Haitao Zhang, 2022. "Cryo-EM structures of human bradykinin receptor-Gq proteins complexes," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:544:y:2017:i:7650:d:10.1038_nature22035. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.