4W9N

Enoyl-acyl carrier protein-reductase domain from human fatty acid synthase complexed with triclosan

Summary for 4W9N

• Entry DOI: 10.2210/pdb4w9n/pdb
• Related: 4W82
• Descriptor: Enoyl-[acyl-carrier-protein] reductase, IMIDAZOLE, CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: fatty acid synthase, fatty acid metabolism, nadph-dependent, enoyl reductase, oxidoreductase
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm : P49327 P49327
• Total number of polymer chains: 4
• Total formula weight: 148294.73

Authors

Sippel, K.H.,Vyas, N.K.,Sankaran, B.,Quiocho, F.A. (deposition date: 2014-08-27, release date: 2014-10-15, Last modification date: 2023-09-27)

Primary citation

Sippel, K.H.,Vyas, N.K.,Zhang, W.,Sankaran, B.,Quiocho, F.A.
Crystal structure of the human Fatty Acid synthase enoyl-acyl carrier protein-reductase domain complexed with triclosan reveals allosteric protein-protein interface inhibition.
J.Biol.Chem., 289:33287-33295, 2014

PubMed Abstract: Human fatty acid synthase (FAS) is a large, multidomain protein that synthesizes long chain fatty acids. Because these fatty acids are primarily provided by diet, FAS is normally expressed at low levels; however, it is highly up-regulated in many cancers. Human enoyl-acyl carrier protein-reductase (hER) is one of the FAS catalytic domains, and its inhibition by drugs like triclosan (TCL) can increase cytotoxicity and decrease drug resistance in cancer cells. We have determined the structure of hER in the presence and absence of TCL. TCL was not bound in the active site, as predicted, but rather at the protein-protein interface (PPI). TCL binding induces a dimer orientation change that causes downstream structural rearrangement in critical active site residues. Kinetics studies indicate that TCL is capable of inhibiting the isolated hER domain with an IC50 of ∼ 55 μM. Given the hER-TCL structure and the inhibition observed in the hER domain, it seems likely that TCL is observed in the physiologically relevant binding site and that it acts as an allosteric PPI inhibitor. TCL may be a viable scaffold for the development of anti-cancer PPI FAS inhibitors.

PubMed: 25301948
DOI: 10.1074/jbc.M114.608547

Experimental method

X-RAY DIFFRACTION (1.84 Å)