Crystal structure of the human fatty acid synthase enoyl-acyl carrier protein-reductase domain complexed with triclosan reveals allosteric protein-protein interface inhibition.

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 tha

SUBMITTER: Sippel KH 

PROVIDER: S-EPMC4246086 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature