title: Sphingosine 1-phosphate analogue recognition and selectivity at S1P4 within the endothelial differentiation gene family of receptors.
abstract: Synergistic computational and experimental studies provided previously unforeseen details concerning the structural basis of S1P (sphingosine 1-phosphate) recognition by the S1P4 G-protein-coupled receptor. Similarly to reports on the S1P1 receptor, cationic and anionic residues in the third transmembrane domain (R3.28 and E3.29 at positions 124 and 125) form ion pairs with the phosphate and ammonium of S1P, and alanine mutations at these positions abolished specific S1P binding, S1P-induced receptor activation and cell migration. Unlike findings on the S1P1 receptor, no cationic residue in the seventh transmembrane domain interacts with the phosphate. Additionally, two previously undiscovered interactions with the S1P polar headgroup have been identified. Trp186 at position 4.64 in the fourth transmembrane domain interacts by a cation-pi interaction with the ammonium group of S1P. Lys204 at position 5.38 forms an ion pair with the S1P. The S1P4 and S1P1 receptors show differences in binding-pocket shape and electrostatic distributions that correlate with the published structure-activity relationships. In particular, the binding pocket of mS1P4 (mouse S1P4) has recognition sites for the anionic phosphate and cationic ammonium groups that are equidistant from the end of the non-polar tail. In contrast, the binding pocket of hS1P1 (human S1P4) places the ammonium recognition site 2 A (1 A=0.1 nm) closer to the end of the non-polar tail than the phosphate recognition site.
authors.affiliation: Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Inagaki
authors.forename: Trucchi T
authors.initials: TT
authors.lastname: Pham
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kohno
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Osborne
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
authors.forename: Abby L
authors.initials: AL
authors.lastname: Parrill
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D006224:Cricetinae; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008246:Lysophospholipids / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D005810:Multigene Family; D009154:Mutation; D049349:Receptors, Lysosphingolipid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C117422:phytosphingosine-1-phosphate; C060504:dihydrosphingosine 1-phosphate; C060506:sphingosine 1-phosphate; D013110:Sphingosine
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