'Crystal' Clear? Lysophospholipid Receptor Structure Insights and Controversies. (November 2018)

• Record Type: Journal Article
• Authors: Blaho, Victoria A.; Chun, Jerold
• Is Part Of: Trends in pharmacological sciences. Volume 39:Number 11(2018)
• Page Start: 953
• Page End: 966
• Publication Date: 2018-11
• Subjects: apolipoprotein M -- autotaxin -- GPCR -- lysophosphatidic acid -- sphingosine 1-phosphate; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2018.08.006
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : Lysophospholipids (LPLs), particularly sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA), are bioactive lipid modulators of cellular homeostasis and pathology. The discovery and characterization of five S1P- and six LPA-specific G protein-coupled receptors (GPCRs), S1P1–5 and LPA1–6, have expanded their known involvement in all mammalian physiological systems. Resolution of the S1P1, LPA1, and LPA6 crystal structures has fueled the growing interest in these receptors and their ligands as targets for pharmacological manipulation. In this review, we have attempted to provide an integrated overview of the three crystallized LPL GPCRs with biochemical and physiological structure–function data. Finally, we provide a novel discussion of how chaperones for LPLs may be considered when extrapolating crystallographic and computational data toward understanding actual biological interactions and phenotypes. Highlights: As major regulators of mammalian physiology, G protein-coupled receptors (GPCRs) for the structurally related lysophospholipids (LPLs) sphingosine 1-phosphate (S1P), lysophosphatidic acid (LPA), as well as other LPLs, are providing new insights into fundamental biology and genuine therapeutics. Despite their structural similarities, GPCRs for S1P and LPA do not show physiological promiscuity, indicating molecular selectivity. In an effort to clarify structural mechanisms underlying ligand recognition and discrimination, the LPL receptors S1P1, LPA1, and most recently, LPA6, have been crystallized, generating hypotheses regarding differential ligand delivery and accommodation. Novel secondary and tertiary structures revealed by the three crystal structures support emerging evidence suggesting that S1P, and possibly LPA, can act as biased agonists when bound to specific protein chaperones.