ArticleThe Journal of biological chemistry2007
Identification of the hydrophobic ligand binding pocket of the S1P1 receptor.
Article in The Journal of biological chemistry, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 55 citations in OpenAlex.
- Computational Analysis of S1PR1 SNPs Reveals Drug Binding Modes Relevant to Multiple Sclerosis Treatment.Pharmaceutics · 2024Article
- Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist.Nature communications · 2024Article
- Structural basis for receptor selectivity and inverse agonism in S1PNature communications · 2022Article
- Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition.Cell research · 2021Article
- Lysophosphatidic acid type 2 receptor agonists in targeted drug development offer broad therapeutic potential.Journal of lipid research · 2019Review
- 'Crystal' Clear? Lysophospholipid Receptor Structure Insights and Controversies.Trends in pharmacological sciences · 2018Review
- Ligand chain length drives activation of lipid G protein-coupled receptors.Scientific reports · 2017Article
- Review
- Dissecting influenza virus pathogenesis uncovers a novel chemical approach to combat the infection.Virology · 2013Review
- Integrating the puzzle pieces: the current atomistic picture of phospholipid-G protein coupled receptor interactions.Biochimica et biophysica acta · 2013Review
- Mitigation of radiation injury by selective stimulation of the LPA(2) receptor.Biochimica et biophysica acta · 2013Article
- Novel selective allosteric and bitopic ligands for the S1P(3) receptor.ACS chemical biology · 2012Article
- Virtual screening for LPA2-specific agonists identifies a nonlipid compound with antiapoptotic actions.Molecular pharmacology · 2012Article
- Crystal structure of a lipid G protein-coupled receptor.Science (New York, N.Y.) · 2012Article
- 4-Methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide: A Potent and Selective Agonist of S1P1.ACS medicinal chemistry letters · 2011Article
- Regulation of mammalian physiology, development, and disease by the sphingosine 1-phosphate and lysophosphatidic acid receptors.Chemical reviews · 2011Review
- FTY720 (Gilenya) phosphate selectivity of sphingosine 1-phosphate receptor subtype 1 (S1P1) G protein-coupled receptor requires motifs in intracellular loop 1 and transmembrane domain 2.The Journal of biological chemistry · 2011Article
- Toward the three-dimensional structure and lysophosphatidic acid binding characteristics of the LPA(4)/p2y(9)/GPR23 receptor: a homology modeling study.Journal of molecular graphics & modelling · 2009Article
- Immunosuppressive human anti-lymphocyte autoantibodies specific for the type 1 sphingosine 1-phosphate receptor.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2009Article
- Arsenic requires sphingosine-1-phosphate type 1 receptors to induce angiogenic genes and endothelial cell remodeling.The American journal of pathology · 2009Article
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
Abstract
Sphingosine 1-phosphate (S1P), a naturally occurring sphingolipid mediator and also a second messenger with growth factor-like actions in almost every cell type, is an endogenous ligand of five G protein-coupled receptors (GPCRs) in the endothelial differentiation gene family. The lack of GPCR crystal structures sets serious limitations to rational drug design and in silico searches for subtype-selective ligands. Here we report on the experimental validation of a computational model of the ligand binding pocket of the S1P1 GPCR surrounding the aliphatic portion of S1P. The extensive mutagenesis-based validation confirmed 18 residues lining the hydrophobic ligand binding pocket, which, combined with the previously validated three head group-interacting residues, now complete the mapping of the S1P ligand recognition site. We identified six mutants (L3.43G/L3.44G, L3.43E/L3.44E, L5.52A, F5.48G, V6.40L, and F6.44G) that maintained wild type [32P]S1P binding with abolished ligand-dependent activation by S1P. These data suggest a role for these amino acids in the conformational transition of S1P1 to its activated state. Three aromatic mutations (F5.48Y, F6.44G, and W6.48A) result in differential activation, by S1P or SEW2871, indicating that structural differences between the two agonists can partially compensate for differences in the amino acid side chain. The now validated ligand binding pocket provided us with a pharmacophore model, which was used for in silico screening of the NCI, National Institutes of Health, Developmental Therapeutics chemical library, leading to the identification of two novel nonlipid agonists of S1P1.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.