Crystallographic study of FABP5 as an intracellular endocannabinoid transporter
- Brookhaven National Laboratory, Upton, NY 11973-5000 (United States)
- Stony Brook University, Stony Brook, NY 11794-5213 (United States)
- Stony Brook University, Stony Brook, NY 1794-3400 (United States)
FABP5 was recently found to intracellularly transport endocannabinoid signaling lipids. The structures of FABP5 complexed with two endocannabinoids and an inhibitor were solved. Human FABP5 was found to dimerize via a domain-swapping mechanism. This work will help in the development of inhibitors to raise endocannabinoid levels. 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.
- OSTI ID:
- 22351304
- Journal Information:
- Acta Crystallographica. Section D: Biological Crystallography, Vol. 70, Issue Pt 2; Other Information: PMCID: PMC3940194; PMID: 24531463; PUBLISHER-ID: xb5074; OAI: oai:pubmedcentral.nih.gov:3940194; Copyright (c) International Union of Crystallography 2014; Country of input: International Atomic Energy Agency (IAEA); ISSN 0907-4449
- Country of Publication:
- Denmark
- Language:
- English
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