Crystallographic study of FABP5 as an intracellular endocannabinoid transporter

Acta Crystallogr D Biol Crystallogr. 2014 Feb;70(Pt 2):290-8. doi: 10.1107/S1399004713026795. Epub 2014 Jan 29.

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.

Keywords: domain swapping; intracellular endocannabinoid transportation; lipid-binding proteins.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Arachidonic Acids / chemistry*
  • Biphenyl Compounds / chemistry*
  • Crystallography, X-Ray
  • Endocannabinoids / chemistry*
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Fatty Acid-Binding Proteins / chemistry*
  • Fatty Acid-Binding Proteins / genetics
  • Glycerides / chemistry*
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Mice
  • Models, Molecular
  • Neoplasm Proteins / chemistry*
  • Neoplasm Proteins / genetics
  • Polyunsaturated Alkamides / chemistry*
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Pyrazoles / chemistry*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics

Substances

  • 2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid
  • Arachidonic Acids
  • Biphenyl Compounds
  • Endocannabinoids
  • FABP5 protein, human
  • Fabp5 protein, mouse
  • Fatty Acid-Binding Proteins
  • Glycerides
  • Neoplasm Proteins
  • Polyunsaturated Alkamides
  • Pyrazoles
  • Recombinant Proteins
  • glyceryl 2-arachidonate
  • anandamide

Associated data

  • PDB/4AZM
  • PDB/4AZN
  • PDB/4AZO
  • PDB/4AZP
  • PDB/4AZQ
  • PDB/4AZR