title: Crystallographic study of FABP5 as an intracellular endocannabinoid transporter.
abstract: In addition to binding intracellular fatty acids, fatty-acid-binding proteins (FABPs) have recently been reported to also transport the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), arachidonic acid derivatives that function as neurotransmitters and mediate a diverse set of physiological and psychological processes. To understand how the endocannabinoids bind to FABPs, the crystal structures of FABP5 in complex with AEA, 2-AG and the inhibitor BMS-309403 were determined. These ligands are shown to interact primarily with the substrate-binding pocket via hydrophobic interactions as well as a common hydrogen bond to the Tyr131 residue. This work advances our understanding of FABP5-endocannabinoid interactions and may be useful for future efforts in the development of small-molecule inhibitors to raise endocannabinoid levels.
authors: Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA.
authors: Benoît
authors: B
authors: Sanson
authors: Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA.
authors: Tao
authors: T
authors: Wang
authors: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5213, USA.
authors: Jing
authors: J
authors: Sun
authors: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5213, USA.
authors: Liqun
authors: L
authors: Wang
authors: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5213, USA.
authors: Martin
authors: M
authors: Kaczocha
authors: Department of Chemistry, Stony Brook University, Stony Brook, NY 1794-3400, USA.
authors: Iwao
authors: I
authors: Ojima
authors: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5213, USA.
authors: Dale
authors: D
authors: Deutsch
authors: Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973-5000, USA.
authors: Huilin
authors: H
authors: Li
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry*; D001713:Biphenyl Compounds / Q000737:chemistry*; D018360:Crystallography, X-Ray; D063388:Endocannabinoids / Q000737:chemistry*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000737:chemistry* / Q000235:genetics; D005989:Glycerides / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics; D053284:Polyunsaturated Alkamides / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics
chemical_list: C559288:2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid; D001095:Arachidonic Acids; D001713:Biphenyl Compounds; D063388:Endocannabinoids; C493412:FABP5 protein, human; C082667:Fabp5 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005989:Glycerides; D009363:Neoplasm Proteins; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D011994:Recombinant Proteins; C094503:glyceryl 2-arachidonate; C078814:anandamide
keywords: domain swapping; intracellular endocannabinoid transportation; lipid-binding proteins