Novel selective allosteric and bitopic ligands for the S1P3 receptor

Euijung Jo, Barun Bhhatarai, Emanuela Repetto, Miguel Guerrero, Sean Riley, Steven J. Brown, Yasushi Kohno, Edward Roberts, Stephan C. Schürer, Hugh Rosen

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


Sphingosine 1-phosphate (S1P) is a lysophospholipid signaling molecule that regulates important biological functions, including lymphocyte trafficking and vascular development, by activating G protein-coupled receptors for S1P, namely, S1P1 through S1P5. Here, we map the S1P3 binding pocket with a novel allosteric agonist (CYM-5541), an orthosteric agonist (S1P), and a novel bitopic antagonist (SPM-242). With a combination of site-directed mutagenesis, ligand competition assay, and molecular modeling, we concluded that S1P and CYM-5541 occupy different chemical spaces in the ligand binding pocket of S1P3. CYM-5541 allowed us to identify an allosteric site where Phe263 is a key gate-keeper residue for its affinity and efficacy. This ligand lacks a polar moiety, and the novel allosteric hydrophobic pocket permits S1P3 selectivity of CYM-5541 within the highly similar S1P receptor family. However, a novel S1P3-selective antagonist, SPM-242, in the S1P3 pocket occupies the ligand binding spaces of both S1P and CYM-5541, showing its bitopic mode of binding. Therefore, our coordinated approach with biochemical data and molecular modeling, based on our recently published S1P1 crystal structure data in a highly conserved set of related receptors with a shared ligand, provides a strong basis for the successful optimization of orthosteric, allosteric, and bitopic modulators of S1P3.

Original languageEnglish (US)
Pages (from-to)1975-1983
Number of pages9
JournalACS Chemical Biology
Issue number12
StatePublished - Dec 21 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine


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