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Crystal Structure of a Lipid G Protein–Coupled Receptor

Science, 17 February 2012
Vol. 335, Issue 6070, p. 851-855
DOI: 10.1126/science.1215904

Crystal Structure of a Lipid G Protein–Coupled Receptor

  1. Michael A. Hanson1,*,
  2. Christopher B. Roth1,
  3. Euijung Jo2,
  4. Mark T. Griffith1,
  5. Fiona L. Scott1,
  6. Greg Reinhart1,
  7. Hans Desale1,
  8. Bryan Clemons1,
  9. Stuart M. Cahalan2,
  10. Stephan C. Schuerer3,
  11. M. Germana Sanna2,
  12. Gye Won Han3,
  13. Peter Kuhn4,
  14. Hugh Rosen2,5,*,,
  15. Raymond C. Stevens3,*,
  1. 1Receptos, 10835 Road to the Cure, Suite 205, San Diego, CA 92121, USA.
  2. 2Department of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
  3. 3Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
  4. 4Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
  5. 5The Scripps Research Institute Molecular Screening Center, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
  1. *To whom correspondence should be addressed. E-mail: mhanson{at} (M.A.H.), stevens{at} (R.C.S.), hrosen{at} (H.R.)
  1. These authors contributed equally to this work.


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.

  • Received for publication 28 October 2011.
  • Accepted for publication 22 December 2011.


M. A. Hanson, C. B. Roth, E. Jo, M. T. Griffith, F. L. Scott, G. Reinhart, H. Desale, B. Clemons, S. M. Cahalan, S. C. Schuerer, M. G. Sanna, G. W. Han, P. Kuhn, H. Rosen, and R. C. Stevens, Crystal Structure of a Lipid G Protein–Coupled Receptor. Science 335, 851-855 (2012).

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