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Structural basis for GPR40 allosteric agonism and incretin stimulation.
Ho, Joseph D; Chau, Betty; Rodgers, Logan; Lu, Frances; Wilbur, Kelly L; Otto, Keith A; Chen, Yanyun; Song, Min; Riley, Jonathan P; Yang, Hsiu-Chiung; Reynolds, Nichole A; Kahl, Steven D; Lewis, Anjana Patel; Groshong, Christopher; Madsen, Russell E; Conners, Kris; Lineswala, Jayana P; Gheyi, Tarun; Saflor, Melbert-Brian Decipulo; Lee, Matthew R; Benach, Jordi; Baker, Kenton A; Montrose-Rafizadeh, Chahrzad; Genin, Michael J; Miller, Anne R; Hamdouchi, Chafiq.
Afiliação
  • Ho JD; Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA. ho_joseph_d@lilly.com.
  • Chau B; Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA.
  • Rodgers L; Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA.
  • Lu F; Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA.
  • Wilbur KL; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
  • Otto KA; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
  • Chen Y; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
  • Song M; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
  • Riley JP; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
  • Yang HC; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
  • Reynolds NA; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
  • Kahl SD; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
  • Lewis AP; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
  • Groshong C; Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA.
  • Madsen RE; Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA.
  • Conners K; Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA.
  • Lineswala JP; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
  • Gheyi T; Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA.
  • Saflor MD; Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA.
  • Lee MR; Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA.
  • Benach J; Lilly Research Laboratories Collaborative Access Team, Advanced Photon Source, Argonne National Laboratory, Building 438A, 9700 S. Cass Avenue, Lemont, IL, 60439, USA.
  • Baker KA; Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA.
  • Montrose-Rafizadeh C; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
  • Genin MJ; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
  • Miller AR; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
  • Hamdouchi C; Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA. hamdouchi_chafiq@lilly.com.
Nat Commun ; 9(1): 1645, 2018 04 25.
Article em En | MEDLINE | ID: mdl-29695780
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores Acoplados a Proteínas G / Diabetes Mellitus Tipo 2 / Incretinas / Secreção de Insulina / Hipoglicemiantes Limite: Animals / Humans / Male Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores Acoplados a Proteínas G / Diabetes Mellitus Tipo 2 / Incretinas / Secreção de Insulina / Hipoglicemiantes Limite: Animals / Humans / Male Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos