Crystal Structure of a Lipid G Protein-Coupled Receptor

被引：0

作者：

Hanson, Michael A. ^{[1
]}

Roth, Christopher B. ^{[1
]}

Jo, Euijung ^{[2
]}

Griffith, Mark T. ^{[1
]}

Scott, Fiona L. ^{[1
]}

Reinhart, Greg ^{[1
]}

Desale, Hans ^{[1
]}

Clemons, Bryan ^{[1
]}

Cahalan, Stuart M. ^{[2
]}

Schuerer, Stephan C. ^{[3
]}

Sanna, M. Germana ^{[2
]}

Han, Gye Won ^{[3
]}

Kuhn, Peter ^{[4
]}

Rosen, Hugh ^{[2
,5
]}

Stevens, Raymond C. ^{[3
]}

机构：

[1] Receptos, San Diego, CA 92121 USA

[2] Scripps Res Inst, Dept Biol Chem, La Jolla, CA 92037 USA

[3] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA

[4] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA

[5] Scripps Res Inst, Mol Screening Ctr, La Jolla, CA 92037 USA

来源：

SCIENCE | 2012年 / 335卷 / 6070期

关键词：

LIGAND-BINDING POCKET; S1P(1); IDENTIFICATION; AGONIST; GPCR; RHODOPSIN; DISCOVERY; EDG1;

D O I：

10.1126/science.1215904

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：851 / 855

页数：5

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