5UR9

Enantiomer-Specific Binding of the Potent Antinociceptive Agent SBFI-26 to Anandamide transporters FABP5

Summary for 5UR9

• Entry DOI: 10.2210/pdb5ur9/pdb
• Related: 5URA
• Descriptor: Fatty acid-binding protein, epidermal, (1S,2S,3S,4S)-3-{[(naphthalen-1-yl)oxy]carbonyl}-2,4-diphenylcyclobutane-1-carboxylic acid, SULFATE ION, ... (6 entities in total)
• Functional Keywords: inhibitor, lipid binding protein-inhibitor complex, lipid binding protein/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 8
• Total formula weight: 129952.62

Authors

Hsu, H.-C.,Li, H. (deposition date: 2017-02-09, release date: 2017-08-23, Last modification date: 2023-10-04)

Primary citation

Hsu, H.C.,Tong, S.,Zhou, Y.,Elmes, M.W.,Yan, S.,Kaczocha, M.,Deutsch, D.G.,Rizzo, R.C.,Ojima, I.,Li, H.
The Antinociceptive Agent SBFI-26 Binds to Anandamide Transporters FABP5 and FABP7 at Two Different Sites.
Biochemistry, 56:3454-3462, 2017

PubMed Abstract: Human FABP5 and FABP7 are intracellular endocannabinoid transporters. SBFI-26 is an α-truxillic acid 1-naphthyl monoester that competitively inhibits the activities of FABP5 and FABP7 and produces antinociceptive and anti-inflammatory effects in mice. The synthesis of SBFI-26 yields several stereoisomers, and it is not known how the inhibitor binds the transporters. Here we report co-crystal structures of SBFI-26 in complex with human FABP5 and FABP7 at 2.2 and 1.9 Å resolution, respectively. We found that only (S)-SBFI-26 was present in the crystal structures. The inhibitor largely mimics the fatty acid binding pattern, but it also has several unique interactions. Notably, the FABP7 complex corroborates key aspects of the ligand binding pose at the canonical site previously predicted by virtual screening. In FABP5, SBFI-26 was unexpectedly found to bind at the substrate entry portal region in addition to binding at the canonical ligand-binding pocket. Our structural and binding energy analyses indicate that both R and S forms appear to bind the transporter equally well. We suggest that the S enantiomer observed in the crystal structures may be a result of the crystallization process selectively incorporating the (S)-SBFI-26-FABP complexes into the growing lattice, or that the S enantiomer may bind to the portal site more rapidly than to the canonical site, leading to an increased local concentration of the S enantiomer for binding to the canonical site. Our work reveals two binding poses of SBFI-26 in its target transporters. This knowledge will guide the development of more potent FABP inhibitors based upon the SBFI-26 scaffold.

PubMed: 28632393
DOI: 10.1021/acs.biochem.7b00194

Experimental method

X-RAY DIFFRACTION (2.19800343737 Å)