title: 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 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.
authors.affiliation: From the Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030 and.
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Sippel
authors.affiliation: From the Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030 and.
authors.forename: Nand K
authors.initials: NK
authors.lastname: Vyas
authors.affiliation: From the Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030 and.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: the Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, California 94720.
authors.forename: Banumathi
authors.initials: B
authors.lastname: Sankaran
authors.affiliation: From the Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030 and faq@bcm.edu.
authors.forename: Florante A
authors.initials: FA
authors.lastname: Quiocho
mesh_terms: D000494:Allosteric Regulation; D018360:Crystallography, X-Ray; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000737:chemistry*; D064429:Fatty Acid Synthases / Q000737:chemistry*; D054872:Fatty Acid Synthesis Inhibitors / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014260:Triclosan / Q000737:chemistry*
chemical_list: D054872:Fatty Acid Synthesis Inhibitors; D014260:Triclosan; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH); D064429:Fatty Acid Synthases
keywords: Allosteric Inhibitor; Cancer Therapy; Drug Action; Enoyl-acyl Carrier Protein-Reductase; Fatty Acid Synthase (FAS); Protein-Protein Interaction; Triclosan; X-ray Crystallography