Sphingosine-1-phosphate (S1P) is a bioactive lipid with diverse functions, including cell proliferation, differentiation, angiogenesis, chemotaxis, and migration. Many of these activities are mediated through five closely related G-protein-coupled receptors (GPCR) of the S1P receptor (S1PR) family. Because of the technical challenges in crystallization of membrane-bound proteins, S1PR structures have not become publicly available. Instead, homology models were built based on a theoretical model of the retina pigment rhodopsin, which is a GPCR with a covalently bound ligand (Parrill, A. L. et al. J. Biol. Chem. 2000, 275, 39379). Recently, new techniques in crystallization have made more GPCR structures available, including those in complex with their agonist, antagonist, or inverse agonist. These structures provide more realistic basis for building S1PR structural models, and at the same time raise a new question about which structure to use in drug design and virtual screening. In this presentation, two structural models of S1PR subtype 5 (S1PR5, Kothapalli, R, Kusmartseva I, and Loughran Jr T. P. et al. Biochim. Biophys. Acta 2002, 1579, 117) are constructed based on crystal structures of β2-adrenergic receptor (β2AR), one of the most extensively studied GPCR. A nanobody-stabilized active state of β2AR (Soren, G. F. et al. Nature 2011, 469, 175) and an inactive state of β2AR in complex with its partial inverse agonist (Cherezov, V. et al. Science 2007, 318, 1258; Hanson, M. A. et al. Structure 2008, 16, 897) are used in building the two models, which are subsequently tested by in silico docking of their known ligands. The models based on active and inactive β2AR are used in virtual screening to find potential activators and inhibitors, respectively. Results from the two models are compared and their different applications are discussed.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A132.