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Crystal structure of the α1B-adrenergic receptor reveals molecular determinants of selective ligand recognition

Author

Listed:
  • Mattia Deluigi

    (University of Zurich)

  • Lena Morstein

    (University of Zurich)

  • Matthias Schuster

    (University of Zurich)

  • Christoph Klenk

    (University of Zurich)

  • Lisa Merklinger

    (University of Zurich
    Technical University of Denmark)

  • Riley R. Cridge

    (The University of Melbourne)

  • Lazarus A. Zhang

    (The University of Melbourne
    The University of Melbourne)

  • Alexander Klipp

    (University of Zurich
    ETH Zurich)

  • Santiago Vacca

    (University of Zurich)

  • Tasneem M. Vaid

    (Department of Pharmaceutical Sciences, University of Illinois at Chicago)

  • Peer R. E. Mittl

    (University of Zurich)

  • Pascal Egloff

    (University of Zurich)

  • Stefanie A. Eberle

    (University of Zurich
    University of Copenhagen)

  • Oliver Zerbe

    (University of Zurich)

  • David K. Chalmers

    (Monash University)

  • Daniel J. Scott

    (The University of Melbourne
    The University of Melbourne)

  • Andreas Plückthun

    (University of Zurich)

Abstract

α-adrenergic receptors (αARs) are G protein-coupled receptors that regulate vital functions of the cardiovascular and nervous systems. The therapeutic potential of αARs, however, is largely unexploited and hampered by the scarcity of subtype-selective ligands. Moreover, several aminergic drugs either show off-target binding to αARs or fail to interact with the desired subtype. Here, we report the crystal structure of human α1BAR bound to the inverse agonist (+)-cyclazosin, enabled by the fusion to a DARPin crystallization chaperone. The α1BAR structure allows the identification of two unique secondary binding pockets. By structural comparison of α1BAR with α2ARs, and by constructing α1BAR-α2CAR chimeras, we identify residues 3.29 and 6.55 as key determinants of ligand selectivity. Our findings provide a basis for discovery of α1BAR-selective ligands and may guide the optimization of aminergic drugs to prevent off-target binding to αARs, or to elicit a selective interaction with the desired subtype.

Suggested Citation

  • Mattia Deluigi & Lena Morstein & Matthias Schuster & Christoph Klenk & Lisa Merklinger & Riley R. Cridge & Lazarus A. Zhang & Alexander Klipp & Santiago Vacca & Tasneem M. Vaid & Peer R. E. Mittl & Pa, 2022. "Crystal structure of the α1B-adrenergic receptor reveals molecular determinants of selective ligand recognition," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27911-3
    DOI: 10.1038/s41467-021-27911-3
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    Cited by:

    1. Christoph Klenk & Maria Scrivens & Anina Niederer & Shuying Shi & Loretta Mueller & Elaine Gersz & Maurice Zauderer & Ernest S. Smith & Ralf Strohner & Andreas Plückthun, 2023. "A Vaccinia-based system for directed evolution of GPCRs in mammalian cells," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Yosuke Toyoda & Angqi Zhu & Fang Kong & Sisi Shan & Jiawei Zhao & Nan Wang & Xiaoou Sun & Linqi Zhang & Chuangye Yan & Brian K. Kobilka & Xiangyu Liu, 2023. "Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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