Error message

No crossref credentials set for sci

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}receptos.com (M.A.H.), stevens{at}scripps.edu (R.C.S.), hrosen{at}scripps.edu (H.R.)
  1. These authors contributed equally to this work.

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.

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

Citation:

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).

Mutation analysis and molecular modeling for the investigation of ligand-binding modes of GPR84
Y. Nikaido, Y. Koyama, Y. Yoshikawa, T. Furuya, and S. Takeda
J Biochem 157, 311-320 (1 May 2015)

S1PR1 Tyr143 phosphorylation downregulates endothelial cell surface S1PR1 expression and responsiveness
A. Chavez, T. T. Schmidt, P. Yazbeck, C. Rajput, B. Desai, S. Sukriti, K. Giantsos-Adams, N. Knezevic, A. B. Malik, D. Mehta et al.
J. Cell Sci. 128, 878-887 (1 March 2015)

Smoothened Goes Molecular: New Pieces in the Hedgehog Signaling Puzzle
J. M. McCabe, and D. J. Leahy
J Biol Chem 290, 3500-3507 (6 February 2015)

Individual variation of human S1P1 coding sequence leads to heterogeneity in receptor function and drug interactions
H. Obinata, S. Gutkind, J. Stitham, T. Okuno, T. Yokomizo, J. Hwa, and T. Hla
J. Lipid Res. 55, 2665-2675 (1 December 2014)

Structural Basis of G Protein-coupled Receptor-Gi Protein Interaction: FORMATION OF THE CANNABINOID CB2 RECEPTOR-Gi PROTEIN COMPLEX
J. S. Mnpotra, Z. Qiao, J. Cai, D. L. Lynch, A. Grossfield, N. Leioatts, D. P. Hurst, M. C. Pitman, Z.-H. Song, P. H. Reggio et al.
J Biol Chem 289, 20259-20272 (18 July 2014)

The Molecular Basis of Ligand Interaction at Free Fatty Acid Receptor 4 (FFA4/GPR120)
B. D. Hudson, B. Shimpukade, G. Milligan, and T. Ulven
J Biol Chem 289, 20345-20358 (18 July 2014)

NMDA receptor structures reveal subunit arrangement and pore architecture
C.-H. Lee, W. Lu, J. C. Michel, A. Goehring, J. Du, X. Song, and E. Gouaux
Nature 511, 191-197 (10 July 2014)

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
Mol. Pharmacol. 85, 608-617 (1 April 2014)

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
J Biol Chem 289, 5846-5859 (28 February 2014)

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, H. H. Seltzman, J. P. Marcu, M. E. Abood, R. A. Ross, and P. H. Reggio
J Biol Chem 289, 5828-5845 (28 February 2014)

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
J Biol Chem 289, 3689-3702 (7 February 2014)

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
Plant Physiol. 164, 287-307 (1 January 2014)

GPCRDB: an information system for G protein-coupled receptors
V. Isberg, B. Vroling, R. van der Kant, K. Li, G. Vriend, and D. Gloriam
Nucleic Acids Res 42, D422-D425 (1 January 2014)

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
J Biol Chem 288, 32449-32465 (8 November 2013)

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.
Pharmacol. Rev. 65, 967-986 (17 May 2013)

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
J. Pharmacol. Exp. Ther. 345, 189-197 (1 May 2013)

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond
D. K. Breslow, D. M. Shore, A. Kapur, M. Trznadel, A. Makriyannis, P. H. Reggio, and M. E. Abood
Cold Spring Harb. Perspect. Biol. 5, a013326-a013326 (1 April 2013)

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
J Biol Chem 288, 8187-8197 (22 March 2013)

Preparation of purified GPCRs for structural studies
R. M. Cooke, M. Koglin, J. C. Errey, and F. H. Marshall
Biochm. Soc. Trans. 41, 185-190 (1 February 2013)

Insights into the molecular evolution of oxytocin receptor ligand binding
J. Koehbach, T. Stockner, C. Bergmayr, M. Muttenthaler, and C. W. Gruber
Biochm. Soc. Trans. 41, 197-204 (1 February 2013)

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
Mol. Pharmacol. 83, 316-321 (1 February 2013)

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
J Biol Chem 288, 1814-1827 (18 January 2013)

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
J. Neurosci. 33, 201-213 (2 January 2013)

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
Mol. Pharmacol. 83, 206-216 (1 January 2013)

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
Protein Eng Des Sel 26, 59-71 (1 January 2013)

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
Proc. Natl. Acad. Sci. USA 109, 19988-19993 (4 December 2012)

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.
Mol. Pharmacol. 82, 1162-1173 (1 December 2012)

Pleiotropic functions of the transmembrane domain 6 of human melanocortin-4 receptor
H. Huang, and Y.-X. Tao
J Mol Endocrinol 49, 237-248 (30 October 2012)

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, M. M. Rosenkilde et al.
J Biol Chem 287, 35470-35483 (12 October 2012)

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
J Biol Chem 287, 33488-33502 (28 September 2012)

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.
Proc. Natl. Acad. Sci. USA 109, 14393-14398 (4 September 2012)

New Insights for Drug Design from the X-Ray Crystallographic Structures of G-Protein-Coupled Receptors
K. A. Jacobson, and S. Costanzi
Mol. Pharmacol. 82, 361-371 (1 September 2012)

A simple guide to biochemical approaches for analyzing protein-lipid interactions
H. Zhao, and P. Lappalainen
Mol. Biol. Cell 23, 2823-2830 (1 August 2012)

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.
Science 337, 232-236 (13 July 2012)

Structure of the First Sphingosine 1-Phosphate Receptor
A. L. Parrill, S. Lima, and S. Spiegel
Sci Signal 5, pe23-pe23 (22 May 2012)

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