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Title: Crystal Structure of a Lipid G Protein-Coupled Receptor

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.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ;  [1]
  1. Scripps
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1036025
Resource Type:
Journal Article
Journal Name:
Science
Additional Journal Information:
Journal Volume: 335; Journal Issue: 6070; Journal ID: ISSN 0036-8075
Publisher:
AAAS
Country of Publication:
United States
Language:
ENGLISH
Subject:
36 MATERIALS SCIENCE; CRYSTAL STRUCTURE; LIPIDS; LYMPHOCYTES; MODULATION; MUTAGENESIS; SIMULATION; STRUCTURE-ACTIVITY RELATIONSHIPS

Citation Formats

Hanson, Michael A, Roth, Christopher B, Jo, Euijung, Griffith, Mark T, Scott, Fiona L, Reinhart, Greg, Desale, Hans, Clemons, Bryan, Cahalan, Stuart M, Schuerer, Stephan C, Sanna, M Germana, Han, Gye Won, Kuhn, Peter, Rosen, Hugh, Stevens, Raymond C, and Receptos). Crystal Structure of a Lipid G Protein-Coupled Receptor. United States: N. p., 2012. Web. doi:10.1126/science.1215904.
Hanson, Michael A, Roth, Christopher B, Jo, Euijung, Griffith, Mark T, Scott, Fiona L, Reinhart, Greg, Desale, Hans, Clemons, Bryan, Cahalan, Stuart M, Schuerer, Stephan C, Sanna, M Germana, Han, Gye Won, Kuhn, Peter, Rosen, Hugh, Stevens, Raymond C, & Receptos). Crystal Structure of a Lipid G Protein-Coupled Receptor. United States. https://doi.org/10.1126/science.1215904
Hanson, Michael A, Roth, Christopher B, Jo, Euijung, Griffith, Mark T, Scott, Fiona L, Reinhart, Greg, Desale, Hans, Clemons, Bryan, Cahalan, Stuart M, Schuerer, Stephan C, Sanna, M Germana, Han, Gye Won, Kuhn, Peter, Rosen, Hugh, Stevens, Raymond C, and Receptos). 2012. "Crystal Structure of a Lipid G Protein-Coupled Receptor". United States. https://doi.org/10.1126/science.1215904.
@article{osti_1036025,
title = {Crystal Structure of a Lipid G Protein-Coupled Receptor},
author = {Hanson, Michael A and Roth, Christopher B and Jo, Euijung and Griffith, Mark T and Scott, Fiona L and Reinhart, Greg and Desale, Hans and Clemons, Bryan and Cahalan, Stuart M and Schuerer, Stephan C and Sanna, M Germana and Han, Gye Won and Kuhn, Peter and Rosen, Hugh and Stevens, Raymond C and Receptos)},
abstractNote = {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.},
doi = {10.1126/science.1215904},
url = {https://www.osti.gov/biblio/1036025}, journal = {Science},
issn = {0036-8075},
number = 6070,
volume = 335,
place = {United States},
year = {Thu Mar 01 00:00:00 EST 2012},
month = {Thu Mar 01 00:00:00 EST 2012}
}