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; Chafiq Hamdouchi

doi:10.1038/s41467-017-01240-w

Structural basis for GPR40 allosteric agonism and incretin stimulation

Nat Commun. 2018 Apr 25;9(1):1645. doi: 10.1038/s41467-017-01240-w.

Authors

Joseph D Ho¹, Betty Chau², Logan Rodgers², Frances Lu², Kelly L Wilbur³, Keith A Otto³, Yanyun Chen³, Min Song³, Jonathan P Riley³, Hsiu-Chiung Yang³, Nichole A Reynolds³, Steven D Kahl³, Anjana Patel Lewis³, Christopher Groshong², Russell E Madsen², Kris Conners², Jayana P Lineswala³, Tarun Gheyi², Melbert-Brian Decipulo Saflor², Matthew R Lee², Jordi Benach⁴, Kenton A Baker², Chahrzad Montrose-Rafizadeh³, Michael J Genin³, Anne R Miller³, Chafiq Hamdouchi⁵

Affiliations

¹ Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA. [email protected].
² Lilly Biotechnology Center San Diego, 10290 Campus Point Drive, San Diego, CA, 92121, USA.
³ Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA.
⁴ Lilly Research Laboratories Collaborative Access Team, Advanced Photon Source, Argonne National Laboratory, Building 438A, 9700 S. Cass Avenue, Lemont, IL, 60439, USA.
⁵ Lilly Research Laboratories, Lilly Corporate Center, 355 East Merrill Street, Indianapolis, IN, 46285, USA. [email protected].

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 Gα_q-coupled partial agonist, compound 1 is a dual Gα_q and Gα_s-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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Allosteric Site / genetics
Animals
Benzofurans / pharmacology
Benzofurans / therapeutic use
Crystallography, X-Ray
Diabetes Mellitus, Type 2 / drug therapy*
Diabetes Mellitus, Type 2 / metabolism
Drug Synergism
HEK293 Cells
Humans
Hypoglycemic Agents / pharmacology*
Hypoglycemic Agents / therapeutic use
Incretins / metabolism*
Insulin / metabolism
Insulin Secretion*
Male
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Mice, Knockout
Molecular Docking Simulation
Mutagenesis, Site-Directed
Receptors, G-Protein-Coupled / agonists*
Receptors, G-Protein-Coupled / chemistry
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Sulfones / pharmacology
Sulfones / therapeutic use
gamma-Linolenic Acid / metabolism

Substances

Benzofurans
FFAR1 protein, human
Ffar1 protein, mouse
Hypoglycemic Agents
Incretins
Insulin
Receptors, G-Protein-Coupled
Recombinant Proteins
Sulfones
TAK-875
gamma-Linolenic Acid