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Structural basis for GPR40 allosteric agonism and incretin stimulation

Author

Listed:
  • Joseph D. Ho

    (Lilly Biotechnology Center San Diego)

  • Betty Chau

    (Lilly Biotechnology Center San Diego)

  • Logan Rodgers

    (Lilly Biotechnology Center San Diego)

  • Frances Lu

    (Lilly Biotechnology Center San Diego)

  • Kelly L. Wilbur

    (Lilly Corporate Center)

  • Keith A. Otto

    (Lilly Corporate Center)

  • Yanyun Chen

    (Lilly Corporate Center)

  • Min Song

    (Lilly Corporate Center)

  • Jonathan P. Riley

    (Lilly Corporate Center)

  • Hsiu-Chiung Yang

    (Lilly Corporate Center)

  • Nichole A. Reynolds

    (Lilly Corporate Center)

  • Steven D. Kahl

    (Lilly Corporate Center)

  • Anjana Patel Lewis

    (Lilly Corporate Center)

  • Christopher Groshong

    (Lilly Biotechnology Center San Diego)

  • Russell E. Madsen

    (Lilly Biotechnology Center San Diego)

  • Kris Conners

    (Lilly Biotechnology Center San Diego)

  • Jayana P. Lineswala

    (Lilly Corporate Center)

  • Tarun Gheyi

    (Lilly Biotechnology Center San Diego)

  • Melbert-Brian Decipulo Saflor

    (Lilly Biotechnology Center San Diego)

  • Matthew R. Lee

    (Lilly Biotechnology Center San Diego)

  • Jordi Benach

    (Argonne National Laboratory)

  • Kenton A. Baker

    (Lilly Biotechnology Center San Diego)

  • Chahrzad Montrose-Rafizadeh

    (Lilly Corporate Center)

  • Michael J. Genin

    (Lilly Corporate Center)

  • Anne R. Miller

    (Lilly Corporate Center)

  • Chafiq Hamdouchi

    (Lilly Corporate Center)

Abstract

Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-Å crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Gαq-coupled partial agonist, compound 1 is a dual Gαq and Gαs-coupled full agonist. compound 1 binds in the lipid-rich region of the receptor near intracellular loop 2 (ICL2), in which the stabilization of ICL2 by the ligand is likely the primary mechanism for the enhanced G protein activities. The endogenous free fatty acid (FFA), γ-linolenic acid, can be computationally modeled in this site. Both γ-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site.

Suggested Citation

  • Joseph D. Ho & Betty Chau & Logan Rodgers & Frances Lu & Kelly L. Wilbur & Keith A. Otto & Yanyun Chen & Min Song & Jonathan P. Riley & Hsiu-Chiung Yang & Nichole A. Reynolds & Steven D. Kahl & Anjana, 2018. "Structural basis for GPR40 allosteric agonism and incretin stimulation," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-01240-w
    DOI: 10.1038/s41467-017-01240-w
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    Cited by:

    1. Alexander S. Powers & Aasma Khan & Joseph M. Paggi & Naomi R. Latorraca & Sarah Souza & Jerry Salvo & Jun Lu & Stephen M. Soisson & Jennifer M. Johnston & Adam B. Weinglass & Ron O. Dror, 2024. "A non-canonical mechanism of GPCR activation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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