Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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} (M.A.H.), stevens{at} (R.C.S.), hrosen{at} (H.R.)

Observed Drug-Receptor Association Rates Are Governed by Membrane Affinity: The Importance of Establishing "Micro-Pharmacokinetic/Pharmacodynamic Relationships" at the {beta}2-Adrenoceptor.
D. A. Sykes, C. Parry, J. Reilly, P. Wright, R. A. Fairhurst, and S. J. Charlton (2014)
Mol. Pharmacol. 85, 608-617
   Abstract »    Full Text »    PDF »
Allosteric Modulation of a Cannabinoid G Protein-coupled Receptor: BINDING SITE ELUCIDATION AND RELATIONSHIP TO G PROTEIN SIGNALING.
D. M. Shore, G. L. Baillie, D. H. Hurst, F. Navas III, H. H. Seltzman, J. P. Marcu, M. E. Abood, R. A. Ross, and P. H. Reggio (2014)
J. Biol. Chem. 289, 5828-5845
   Abstract »    Full Text »    PDF »
Pancreatic Polypeptide Is Recognized by Two Hydrophobic Domains of the Human Y4 Receptor Binding Pocket.
X. Pedragosa-Badia, G. R. Sliwoski, E. Dong Nguyen, D. Lindner, J. Stichel, K. W. Kaufmann, J. Meiler, and A. G. Beck-Sickinger (2014)
J. Biol. Chem. 289, 5846-5859
   Abstract »    Full Text »    PDF »
A Membrane-proximal, C-terminal {alpha}-Helix Is Required for Plasma Membrane Localization and Function of the G Protein-coupled Receptor (GPCR) TGR5.
L. Spomer, C. G. W. Gertzen, B. Schmitz, D. Haussinger, H. Gohlke, and V. Keitel (2014)
J. Biol. Chem. 289, 3689-3702
   Abstract »    Full Text »    PDF »
GPCRDB: an information system for G protein-coupled receptors.
V. Isberg, B. Vroling, R. van der Kant, K. Li, G. Vriend, and D. Gloriam (2014)
Nucleic Acids Res. 42, D422-D425
   Abstract »    Full Text »    PDF »
Do Plants Contain G Protein-Coupled Receptors?.
B. Taddese, G. J. G. Upton, G. R. Bailey, S. R. D. Jordan, N. Y. Abdulla, P. J. Reeves, and C. A. Reynolds (2014)
Plant Physiology 164, 287-307
   Abstract »    Full Text »    PDF »
Molecular Basis of Cannabinoid CB1 Receptor Coupling to the G Protein Heterotrimer G{alpha}i{beta}{gamma}: IDENTIFICATION OF KEY CB1 CONTACTS WITH THE C-TERMINAL HELIX {alpha}5 OF G{alpha}i.
J.-Y. Shim, K. H. Ahn, and D. A. Kendall (2013)
J. Biol. Chem. 288, 32449-32465
   Abstract »    Full Text »    PDF »
International Union of Basic and Clinical Pharmacology. LXXXVIII. G Protein-Coupled Receptor List: Recommendations for New Pairings with Cognate Ligands.
A. P. Davenport, S. P. H. Alexander, J. L. Sharman, A. J. Pawson, H. E. Benson, A. E. Monaghan, W. C. Liew, C. P. Mpamhanga, T. I. Bonner, R. R. Neubig, et al. (2013)
Pharmacol. Rev. 65, 967-986
   Abstract »    Full Text »    PDF »
Novel Insights into CB1 Cannabinoid Receptor Signaling: A Key Interaction Identified between the Extracellular-3 Loop and Transmembrane Helix 2.
J. Marcu, D. M. Shore, A. Kapur, M. Trznadel, A. Makriyannis, P. H. Reggio, and M. E. Abood (2013)
J. Pharmacol. Exp. Ther. 345, 189-197
   Abstract »    Full Text »    PDF »
Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond.
D. K. Breslow (2013)
Cold Spring Harb Perspect Biol 5, a013326
   Abstract »    Full Text »    PDF »
Structure of the Human Angiotensin II Type 1 (AT1) Receptor Bound to Angiotensin II from Multiple Chemoselective Photoprobe Contacts Reveals a Unique Peptide Binding Mode.
D. Fillion, J. Cabana, G. Guillemette, R. Leduc, P. Lavigne, and E. Escher (2013)
J. Biol. Chem. 288, 8187-8197
   Abstract »    Full Text »    PDF »
Sphingosine 1-Phosphate Receptor 1 (S1P1) Upregulation and Amelioration of Experimental Autoimmune Encephalomyelitis by an S1P1 Antagonist.
S. M. Cahalan, P. J. Gonzalez-Cabrera, N. Nguyen, M. Guerrero, E. A. G. Cisar, N. B. Leaf, S. J. Brown, E. Roberts, and H. Rosen (2013)
Mol. Pharmacol. 83, 316-321
   Abstract »    Full Text »    PDF »
Conopeptide {rho}-TIA Defines a New Allosteric Site on the Extracellular Surface of the {alpha}1B-Adrenoceptor.
L. Ragnarsson, C.-I. A. Wang, A. Andersson, D. Fajarningsih, T. Monks, A. Brust, K. J. Rosengren, and R. J. Lewis (2013)
J. Biol. Chem. 288, 1814-1827
   Abstract »    Full Text »    PDF »
The Human Bitter Taste Receptor TAS2R10 Is Tailored to Accommodate Numerous Diverse Ligands.
S. Born, A. Levit, M. Y. Niv, W. Meyerhof, and M. Behrens (2013)
J. Neurosci. 33, 201-213
   Abstract »    Full Text »    PDF »
Functional fusions of T4 lysozyme in the third intracellular loop of a G protein-coupled receptor identified by a random screening approach in yeast.
E. Mathew, F.-X. Ding, F. Naider, and M. E. Dumont (2013)
Protein Eng. Des. Sel. 26, 59-71
   Abstract »    Full Text »    PDF »
Extracellular Loop II Modulates GTP Sensitivity of the Prostaglandin EP3 Receptor.
C. Natarajan, A. N. Hata, H. E. Hamm, R. Zent, and R. M. Breyer (2013)
Mol. Pharmacol. 83, 206-216
   Abstract »    Full Text »    PDF »
Predicted structure of agonist-bound glucagon-like peptide 1 receptor, a class B G protein-coupled receptor.
A. Kirkpatrick, J. Heo, R. Abrol, and W. A. Goddard III (2012)
PNAS 109, 19988-19993
   Abstract »    Full Text »    PDF »
Virtual Screening for LPA2-Specific Agonists Identifies a Nonlipid Compound with Antiapoptotic Actions.
G. N. Kiss, J. I. Fells, R. Gupte, S.-C. Lee, J. Liu, N. Nusser, K. G. Lim, R. M. Ray, F.-T. Lin, A. L. Parrill, et al. (2012)
Mol. Pharmacol. 82, 1162-1173
   Abstract »    Full Text »    PDF »
Pleiotropic functions of the transmembrane domain 6 of human melanocortin-4 receptor.
H. Huang and Y.-X. Tao (2012)
J. Mol. Endocrinol. 49, 237-248
   Abstract »    Full Text »    PDF »
Molecular Characterization of Oxysterol Binding to the Epstein-Barr Virus-induced Gene 2 (GPR183).
T. Benned-Jensen, C. Norn, S. Laurent, C. M. Madsen, H. M. Larsen, K. N. Arfelt, R. M. Wolf, T. Frimurer, A. W. Sailer, and M. M. Rosenkilde (2012)
J. Biol. Chem. 287, 35470-35483
   Abstract »    Full Text »    PDF »
Modulation of Constitutive Activity and Signaling Bias of the Ghrelin Receptor by Conformational Constraint in the Second Extracellular Loop.
J. Mokrosinski, T. M. Frimurer, B. Sivertsen, T. W. Schwartz, and B. Holst (2012)
J. Biol. Chem. 287, 33488-33502
   Abstract »    Full Text »    PDF »
Molecular basis for negative regulation of the glucagon receptor.
C. M. Koth, J. M. Murray, S. Mukund, A. Madjidi, A. Minn, H. J. Clarke, T. Wong, V. Chiang, E. Luis, A. Estevez, et al. (2012)
PNAS 109, 14393-14398
   Abstract »    Full Text »    PDF »
New Insights for Drug Design from the X-Ray Crystallographic Structures of G-Protein-Coupled Receptors.
K. A. Jacobson and S. Costanzi (2012)
Mol. Pharmacol. 82, 361-371
   Abstract »    Full Text »    PDF »
A simple guide to biochemical approaches for analyzing protein-lipid interactions.
H. Zhao and P. Lappalainen (2012)
Mol. Biol. Cell 23, 2823-2830
   Abstract »    Full Text »    PDF »
Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions.
W. Liu, E. Chun, A. A. Thompson, P. Chubukov, F. Xu, V. Katritch, G. W. Han, C. B. Roth, L. H. Heitman, A. P. IJzerman, et al. (2012)
Science 337, 232-236
   Abstract »    Full Text »    PDF »
Structure of the First Sphingosine 1-Phosphate Receptor.
A. L. Parrill, S. Lima, and S. Spiegel (2012)
Science Signaling 5, pe23
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882