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Structure of class B GPCR corticotropin-releasing factor receptor 1

Author

Listed:
  • Kaspar Hollenstein

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK)

  • James Kean

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK)

  • Andrea Bortolato

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK)

  • Robert K. Y. Cheng

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK)

  • Andrew S. Doré

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK)

  • Ali Jazayeri

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK)

  • Robert M. Cooke

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK)

  • Malcolm Weir

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK)

  • Fiona H. Marshall

    (Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City, AL7 3AX, UK)

Abstract

Structural analysis of class B G-protein-coupled receptors (GPCRs), cell-surface proteins that respond to peptide hormones, has been restricted to the amino-terminal extracellular domain, thus providing little understanding of the membrane-spanning signal transduction domain. The corticotropin-releasing factor receptor type 1 is a class B receptor which mediates the response to stress and has been considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of the human corticotropin-releasing factor receptor type 1 in complex with the small-molecule antagonist CP-376395. The structure provides detailed insight into the architecture of class B receptors. Atomic details of the interactions of the receptor with the non-peptide ligand that binds deep within the receptor are described. This structure provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism.

Suggested Citation

  • Kaspar Hollenstein & James Kean & Andrea Bortolato & Robert K. Y. Cheng & Andrew S. Doré & Ali Jazayeri & Robert M. Cooke & Malcolm Weir & Fiona H. Marshall, 2013. "Structure of class B GPCR corticotropin-releasing factor receptor 1," Nature, Nature, vol. 499(7459), pages 438-443, July.
    • Handle: RePEc:nat:nature:v:499:y:2013:i:7459:d:10.1038_nature12357
    DOI: 10.1038/nature12357
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    Cited by:

    1. Lior Peri & Donna Matzov & Dominic R. Huxley & Alon Rainish & Fabrizio Fierro & Liel Sapir & Tara Pfeiffer & Lukas Waterloo & Harald Hübner & Yoav Peleg & Peter Gmeiner & Peter J. McCormick & Dorothee, 2024. "A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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