title: Towards selective lysophospholipid GPCR modulators.
abstract: G-protein-coupled receptors (GPCRs) that recognize the lysophospholipids (LPLs) are grouped into two phylogenetically distinct families: the endothelial differentiation gene (Edg) and non-Edg GPCRs. Owing to their more recent identification, and hindered by a lack of selective pharmacological tools, our understanding of the functions and signaling pathways of the non-Edg GPCRs is still in its infancy. Targeting the non-conserved allosteric binding sites of the LPL GPCRs shows particular promise for the development of selective modulators by structure-based drug design. However, only one Edg GPCR (S1PR1) structure has been determined to date, and it has low sequence identity with the non-Edg GPCRs (<20%). Thus, a representative structure of a non-Edg GPCR remains a pressing objective for selective structure-based drug design. Obtaining selective modulators targeting the non-Edg receptors would help to unravel the biology behind these novel GPCRs and potentially will support therapeutic treatment of diseases such as cancer, inflammation, and neuropsychiatric disorders.
authors.affiliation: Division of Chemistry and Structural Biology, The University of Queensland, Institute for Molecular Bioscience, St Lucia, Brisbane, QLD 4072, Australia. Electronic address: j.archbold@imb.uq.edu.au.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Archbold
authors.affiliation: Division of Chemistry and Structural Biology, The University of Queensland, Institute for Molecular Bioscience, St Lucia, Brisbane, QLD 4072, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martin
authors.affiliation: Division of Molecular and Cell Biology, The University of Queensland, Institute for Molecular Bioscience, St Lucia, Brisbane, QLD 4072, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
mesh_terms: D001665:Binding Sites; D016503:Drug Delivery Systems; D006801:Humans; D008958:Models, Molecular; D049312:Receptors, Lysophospholipid / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D049312:Receptors, Lysophospholipid
keywords: G-protein-coupled receptors (GPCRs); GPCR structure; endothelial-derived growth factor (Edg); lysophosphatidic acid (LPA); sphingosine 1-phosphate (S1P)