title: Endogenous lipid activated G protein-coupled receptors: emerging structural features from crystallography and molecular dynamics simulations.
abstract: Class A G-protein coupled receptors (GPCRs) are thought to have a common topology that includes seven transmembrane alpha helices (TMHs) that are arranged to form a closed bundle. This bundle forms the ligand binding pocket into which ligands are commonly thought to enter via the extracellular milieu. This ligand approach direction makes sense for GPCRs that have small positively charged ligands, such as the beta-2-adrenergic or the dopamine D2 receptor. However, there is a growing sub-group of Class A GPCRs that bind lipid-derived endogenous ligands, such as the cannabinoid CB1 and CB2 receptors (with endogenous ligands, N-arachidonoylethanolamine (anandamide) and sn-2-arachidonylglycerol (2-AG)) and the S1P1-5 receptors (with endogenous ligand, sphingosine-1-phosphate). Even the widely studied Class A GPCR, rhodopsin, binds a highly lipophillic chromophore (11-cis-retinal). For these receptors, ligand approach from the extracellular milieu has seemed unlikely given that the ligands of these receptors readily partition into lipid or are actually synthesized in the lipid bilayer. The recent X-ray-crystal structure of the sub-type 1 sphingosine-1-phosphate receptor (S1P1) provides important information on the key structural variations that may be the hallmarks for a Class A GPCR that binds lipid-derived ligands. These include an extracellular domain that is closed off to the extracellular milieu and the existence of an opening between transmembrane helices that may serve as a portal for ligand entry via the lipid bilayer. This review examines structural aspects that the cannabinoid receptors may share with the S1P1 receptor based upon sequence homology. This review also examines experimental and simulation results that suggest ligand entry via a lipid portal is quite likely for this emerging sub-group.
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina Greensboro, Greensboro, NC 27402, USA.
authors.forename: Dow P
authors.initials: DP
authors.lastname: Hurst
authors.forename: Marianne
authors.initials: M
authors.lastname: Schmeisser
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Reggio
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D050356:Lipid Metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D043882:Receptors, Cannabinoid / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D043882:Receptors, Cannabinoid