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Science 335 (6070): 851-855

Copyright © 2012 by the American Association for the Advancement of Science

Crystal Structure of a Lipid G Protein–Coupled Receptor

Michael A. Hanson,1,* Christopher B. Roth,1 Euijung Jo,2 Mark T. Griffith,1 Fiona L. Scott,1 Greg Reinhart,1 Hans Desale,1 Bryan Clemons,1 Stuart M. Cahalan,2 Stephan C. Schuerer,3 M. Germana Sanna,2 Gye Won Han,3 Peter Kuhn,4 Hugh Rosen,2,5,*,{dagger} Raymond C. Stevens3,*,{dagger}

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 (S1P1-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 S1P1, resulting in the modulation of immune and stromal cell responses.

1 Receptos, 10835 Road to the Cure, Suite 205, San Diego, CA 92121, USA.
2 Department of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
3 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
4 Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
5 The Scripps Research Institute Molecular Screening Center, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

{dagger} These authors contributed equally to this work.

* To whom correspondence should be addressed. E-mail: mhanson{at}receptos.com (M.A.H.), stevens{at}scripps.edu (R.C.S.), hrosen{at}scripps.edu (H.R.)

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