A sphingosine 1-phosphate receptor 2 selective allosteric agonist |
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Authors: | Hideo Satsu Marie-Therese Schaeffer Miguel Guerrero Adrian Saldana Christina Eberhart Peter Hodder Charmagne Cayanan Stephan Schürer Barun Bhhatarai Ed Roberts Hugh Rosen Steven J Brown |
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Institution: | 1. Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan;2. The Scripps Research Institute Molecular Screening Center, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA;3. Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA;4. Scripps Research Institute Molecular Screening Center, Lead Identification Division, Translational Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA;5. Center for Computational Science, Miller School of Medicine, University of Miami, FL 33136, USA;6. Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA |
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Abstract: | Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-κB-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other S1P receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound. |
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Keywords: | Allosteric Signaling GPCR Sphingosine 1-phosphate Molecular modeling S1PR2 |
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