Structural basis for GPR40 allosteric agonism and incretin stimulation

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 Patel Lewis, Christopher Groshong, Russell E. Madsen, Kris Conners, Jayana P. Lineswala, Tarun Gheyi, Melbert-Brian Decipulo Saflor, Matthew R. Lee, Jordi Benach, Kenton A. Baker, Chahrzad Montrose-Rafizadeh, Michael J. Genin, Anne R. Miller and Chafiq Hamdouchi ()
Additional contact information
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

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-01240-w

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