Crystal structure of a lipid G protein-coupled receptor.

Science
Michael A HansonRaymond C Stevens

Abstract

The lyso-phospholipid sphingosine 1-phosphate modulates lymphocyte trafficking, endothelial development and integrity, heart rate, and vascular tone and maturation by activating G protein-coupled sphingosine 1-phosphate receptors. Here, we present the crystal structure of the sphingosine 1-phosphate receptor 1 fused to T4-lysozyme (S1P(1)-T4L) in complex with an antagonist sphingolipid mimic. Extracellular access to the binding pocket is occluded by the amino terminus and extracellular loops of the receptor. Access is gained by ligands entering laterally between helices I and VII within the transmembrane region of the receptor. This structure, along with mutagenesis, agonist structure-activity relationship data, and modeling, provides a detailed view of the molecular recognition and requirement for hydrophobic volume that activates S1P(1), resulting in the modulation of immune and stromal cell responses.

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Citations

Jul 3, 2013·Journal of Computer-aided Molecular Design·Jan JakubíkVladimír Doležal
Oct 16, 2013·European Journal of Medicinal Chemistry·Ravil R PetrovPhilippe Diaz
Apr 20, 2013·Trends in Biochemical Sciences·Ping-Yee LawHorace H Loh
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Nov 6, 2012·Journal of Chemical Information and Modeling·Thijs Beuming, Woody Sherman
Jun 1, 2013·Journal of Chemical Information and Modeling·Akira ShiraishiYasushi Okuno
Mar 22, 2013·Journal of Chemical Information and Modeling·Hui Wen NgStephen W Doughty
Dec 12, 2012·Nature·Cheng ZhangBrian K Kobilka
Jul 19, 2013·Nature·Kaspar HollensteinFiona H Marshall
Apr 12, 2012·Nature Biotechnology·Meredith Wadman
Jul 20, 2012·Nature Chemical Biology·Sébastien Granier, Brian Kobilka
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