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Novel selective allosteric and bitopic ligands for the S1P(3) receptor

Academic Article
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Overview

authors

  • Jo, E. J.
  • Bhhatarai, B.
  • Repetto, E.
  • Guerrero, M.
  • Riley, S.
  • Brown, S. J.
  • Kohno, Y.
  • Roberts, Edward
  • Schurer, S. C.
  • Rosen, Hugh

publication date

  • December 2012

journal

  • ACS Chemical Biology  Journal

abstract

  • 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, S1P(1) through S1P(5). Here, we map the S1P(3) 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 S1P(3). 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 S1P(3) selectivity of CYM-5541 within the highly similar S1P receptor family. However, a novel S1P(3)-selective antagonist, SPM-242, in the S1P(3) 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 S1P(1) 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 S1P(3).

subject areas

  • Allosteric Site
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Ligands
  • Models, Molecular
  • Phosphorylation
  • Radioligand Assay
  • Receptors, Lysosphingolipid
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Identity

PubMed Central ID

  • PMC3528827

International Standard Serial Number (ISSN)

  • 1554-8929

Digital Object Identifier (DOI)

  • 10.1021/cb300392z

PubMed ID

  • 22971058
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Additional Document Info

start page

  • 1975

end page

  • 1983

volume

  • 7

issue

  • 12

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