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A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist

Author

Listed:
  • Herman Schreuder

    (Marion Merrell Dow Research Institute
    Hoechst AG)

  • Chantal Tardif

    (Marion Merrell Dow Research Institute
    Synthelabo Biomoleculaire)

  • Susanne Trump-Kallmeyer

    (Marion Merrell Dow Research Institute
    Parke Davis Pharmaceutical Research)

  • Adolfo Soffientini

    (Lepetit Research Centre)

  • Edoardo Sarubbi

    (Lepetit Research Centre)

  • Ann Akeson

    (Hoechst Marion Roussel Inc.)

  • Terry Bowlin

    (Lepetit Research Centre
    Hoechst Marion Roussel Inc.
    Biochem Therapeutice)

  • Stephen Yanofsky

    (Affymax)

  • Ronald W. Barrett

    (Affymax)

Abstract

Inflammation, regardless of whether it is provoked by infection or by tissue damage, starts with the activation of macrophages which initiate a cascade of inflammatory responses by producing the cytokines interleukin-1 (IL-1) and tumour necrosis factor-α (ref. 1). Three naturally occurring ligands for the IL-1 receptor (IL1R) exist: the agonists IL-1α and IL-lβ and the IL-1-receptor antagonist IL1RA (ref. 2). IL-1 is the only cytokine for which a naturally occurring antagonist is known. Here we describe the crystal structure at 2.7 Å resolution of the soluble extracellular part of type-I IL1R complexed with IL1RA. The receptor consists of three immunoglobulin-like domains. Domains 1 and 2 are tightly linked, but domain three is completely separate and connected by a flexible linker. Residues of all three domains contact the antagonist and include the five critical IL1RA residues which were identified by site-directed mutagenesis3. A region that is important for biological function in IL-1β, the 'receptor trigger site', is not in direct contact with the receptor in the IL1RA complex. Modelling studies suggest that this IL-1β trigger site might induce a movement of domain 3.

Suggested Citation

  • Herman Schreuder & Chantal Tardif & Susanne Trump-Kallmeyer & Adolfo Soffientini & Edoardo Sarubbi & Ann Akeson & Terry Bowlin & Stephen Yanofsky & Ronald W. Barrett, 1997. "A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist," Nature, Nature, vol. 386(6621), pages 194-200, March.
    • Handle: RePEc:nat:nature:v:386:y:1997:i:6621:d:10.1038_386194a0
    DOI: 10.1038/386194a0
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    1. Ulrich Hommel & Konstanze Hurth & Jean-Michel Rondeau & Anna Vulpetti & Daniela Ostermeier & Andreas Boettcher & Jacob Peter Brady & Michael Hediger & Sylvie Lehmann & Elke Koch & Anke Blechschmidt & , 2023. "Discovery of a selective and biologically active low-molecular weight antagonist of human interleukin-1β," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Buwei Huang & Brian Coventry & Marta T. Borowska & Dimitrios C. Arhontoulis & Marc Exposit & Mohamad Abedi & Kevin M. Jude & Samer F. Halabiya & Aza Allen & Cami Cordray & Inna Goreshnik & Maggie Ahlr, 2024. "De novo design of miniprotein antagonists of cytokine storm inducers," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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