5KW2

The extra-helical binding site of GPR40 and the structural basis for allosteric agonism and incretin stimulation

Summary for 5KW2

• Entry DOI: 10.2210/pdb5kw2/pdb
• Descriptor: Free fatty acid receptor 1,Lysozyme,Free fatty acid receptor 1, (3~{S})-3-cyclopropyl-3-[2-[1-[2-[2,2-dimethylpropyl-(6-methylpyridin-2-yl)carbamoyl]-5-methoxy-phenyl]piperidin-4-yl]-1-benzofuran-6-yl]propanoic acid (3 entities in total)
• Functional Keywords: g-protein coupled receptor, free fatty acid receptor 1, lipid-binding protein, fatty acid binding protein-hydrolase complex, fatty acid binding protein/hydrolase
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane ; Multi-pass membrane protein : O14842
• Total number of polymer chains: 1
• Total formula weight: 53725.97

Authors

Ho, J.D.,Chau, B.,Rodgers, L.,Lu, F.,Wilbur, K.L.,Otto, K.A.,Chen, Y.,Song, M.,Riley, J.P.,Yang, H.-C.,Reynolds, N.A.,Kahl, S.D.,Lewis, A.P.,Groshong, C.,Madsen, R.E.,Conners, K.,Linswala, J.P.,Gheyi, T.,Saflor, M.D.,Lee, M.R.,Benach, J.,Baker, K.A.,Montrose-Rafizadeh, C.,Genin, M.J.,Miller, A.R.,Hamdouchi, C. (deposition date: 2016-07-15, release date: 2018-05-02, Last modification date: 2024-10-30)

Primary citation

Ho, J.D.,Chau, B.,Rodgers, L.,Lu, F.,Wilbur, K.L.,Otto, K.A.,Chen, Y.,Song, M.,Riley, J.P.,Yang, H.C.,Reynolds, N.A.,Kahl, S.D.,Lewis, A.P.,Groshong, C.,Madsen, R.E.,Conners, K.,Lineswala, J.P.,Gheyi, T.,Saflor, M.D.,Lee, M.R.,Benach, J.,Baker, K.A.,Montrose-Rafizadeh, C.,Genin, M.J.,Miller, A.R.,Hamdouchi, C.
Structural basis for GPR40 allosteric agonism and incretin stimulation.
Nat Commun, 9:1645-1645, 2018

PubMed 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-coupled partial agonist, compound 1 is a dual Gα and Gα-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.

PubMed: 29695780
DOI: 10.1038/s41467-017-01240-w

Experimental method

X-RAY DIFFRACTION (2.76 Å)