ArticleThe Journal of biological chemistry2014
Crystal structure of the human fatty acid synthase enoyl-acyl carrier protein-reductase domain complexed with triclosan reveals allosteric protein-protein interface inhibition.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 24 citations in OpenAlex.
- Statistical analysis of sequential motifs at biologically relevant protein-protein interfaces.Computational and structural biotechnology journal · 2024Article
- Atomic model for core modifying region of human fatty acid synthase in complex with Denifanstat.Nature communications · 2023Article
- In silico studies, synthesis and anticancer activity of novel diphenyl ether-based pyridine derivatives.Molecular diversity · 2019Article
- Characteristics of β-oxidative and reductive metabolism on the acyl side chain of cinnamic acid and its analogues in rats.Acta pharmacologica Sinica · 2019Article
- The architectures of iterative type I PKS and FAS.Natural product reports · 2018Review
- Distribution of triclosan-resistant genes in major pathogenic microorganisms revealed by metagenome and genome-wide analysis.PloS one · 2018Article
- Fatty Acids and Breast Cancer: Make Them on Site or Have Them Delivered.Journal of cellular physiology · 2016Review
- Mycocerosic acid synthase exemplifies the architecture of reducing polyketide synthases.Nature · 2016Article
- Comparative Modeling and Molecular Dynamics Simulation of Substrate Binding in Human Fatty Acid Synthase: Enoyl Reductase and β-Ketoacyl Reductase Catalytic Domains.Genomics & informatics · 2015Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
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.
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