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 (S1P(1)-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 S1P(1), resulting in the modulation of immune and stromal cell responses.
authors.affiliation: Receptos, 10835 Road to the Cure, San Diego, CA 92121, USA. mhanson@receptos.com
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hanson
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Roth
authors.forename: Euijung
authors.initials: E
authors.lastname: Jo
authors.forename: Mark T
authors.initials: MT
authors.lastname: Griffith
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Scott
authors.forename: Greg
authors.initials: G
authors.lastname: Reinhart
authors.forename: Hans
authors.initials: H
authors.lastname: Desale
authors.forename: Bryan
authors.initials: B
authors.lastname: Clemons
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Cahalan
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Schuerer
authors.forename: M Germana
authors.initials: MG
authors.lastname: Sanna
authors.forename: Gye Won
authors.initials: GW
authors.lastname: Han
authors.forename: Peter
authors.initials: P
authors.lastname: Kuhn
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
mesh_terms: D000813:Anilides / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry; D016296:Mutagenesis; D063065:Organophosphonates / Q000737:chemistry; D011487:Protein Conformation; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics
chemical_list: C513113:3-amino-4-(3-hexylphenylamino)-4-oxobutylphosphonic acid; D000813:Anilides; D063065:Organophosphonates; D049349:Receptors, Lysosphingolipid; D011993:Recombinant Fusion Proteins; D009113:Muramidase