Structural basis for GPR40 allosteric agonism and incretin stimulation
| Autor: | Min Song, Christopher Groshong, Frances Lu, Yanyun Chen, Steven D. Kahl, Chahrzad Montrose-Rafizadeh, Jayana Pankaj Lineswala, Melbert-Brian Decipulo Saflor, Nichole A. Reynolds, Michaël Genin, Anjana Patel Lewis, Tarun Gheyi, Hsiu-Chiung Yang, Russell E. Madsen, Betty Chau, Chafiq Hamdouchi, Matthew R. Lee, Kenton A. Baker, Anne Reifel Miller, Joseph D. Ho, Keith A. Otto, Kelly L. Wilbur, K. Conners, Jordi Benach, Jonathan P. Riley, Logan Rodgers |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Agonist endocrine system medicine.drug_class G protein Science Allosteric regulation General Physics and Astronomy Crystallography X-Ray Incretins Partial agonist Article General Biochemistry Genetics and Molecular Biology Receptors G-Protein-Coupled Mice 03 medical and health sciences Free fatty acid receptor 1 Insulin Secretion medicine Animals Humans Hypoglycemic Agents Insulin Sulfones gamma-Linolenic Acid Binding site lcsh:Science Benzofurans Mice Knockout Mice Inbred ICR Multidisciplinary Chemistry Cooperative binding Drug Synergism General Chemistry Ligand (biochemistry) Recombinant Proteins Mice Inbred C57BL Molecular Docking Simulation HEK293 Cells 030104 developmental biology Diabetes Mellitus Type 2 Mutagenesis Site-Directed Biophysics lcsh:Q Allosteric Site |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-11 (2018) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. GPR40 is a G-protein coupled receptor that binds to free fatty acids, mediating insulin and incretin secretion. Here, the authors present the crystal structure of human GPR40 with an agonist bound to an allosteric site located near the lipid-rich region that suggests a mechanism for biased agonism. |
| Databáze: | OpenAIRE |
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