5TZR

GPR40 in complex with partial agonist MK-8666

Summary for 5TZR

• Entry DOI: 10.2210/pdb5tzr/pdb
• Related: 5TZY
• Descriptor: Free fatty acid receptor 1,Endolysin,Free fatty acid receptor 1, SODIUM ION, (5aR,6S,6aS)-3-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy][1,1'-biphenyl]-3-yl}methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylic acid, ... (7 entities in total)
• Functional Keywords: ffar1, partial agonist, 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: 57077.72

Authors

Lu, J.,Byrne, N.,Patel, S.,Sharma, S.,Soisson, S.M. (deposition date: 2016-11-22, release date: 2017-06-07, Last modification date: 2024-11-06)

Primary citation

Lu, J.,Byrne, N.,Wang, J.,Bricogne, G.,Brown, F.K.,Chobanian, H.R.,Colletti, S.L.,Di Salvo, J.,Thomas-Fowlkes, B.,Guo, Y.,Hall, D.L.,Hadix, J.,Hastings, N.B.,Hermes, J.D.,Ho, T.,Howard, A.D.,Josien, H.,Kornienko, M.,Lumb, K.J.,Miller, M.W.,Patel, S.B.,Pio, B.,Plummer, C.W.,Sherborne, B.S.,Sheth, P.,Souza, S.,Tummala, S.,Vonrhein, C.,Webb, M.,Allen, S.J.,Johnston, J.M.,Weinglass, A.B.,Sharma, S.,Soisson, S.M.
Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40.
Nat. Struct. Mol. Biol., 24:570-577, 2017

PubMed Abstract: Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40-MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.

PubMed: 28581512
DOI: 10.1038/nsmb.3417

Experimental method

X-RAY DIFFRACTION (2.2 Å)