ArticleProtein & cell2015
Molecular basis for the inhibition of β-hydroxyacyl-ACP dehydratase HadAB complex from Mycobacterium tuberculosis by flavonoid inhibitors.
Article in Protein & cell, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 35 citations in OpenAlex.
- The Biosynthetic Pathway of Mycolic Acids: Dual-Function Targets for Tuberculosis Therapeutics and Green Steroid Drugs Biomanufacturing.Pharmaceutics · 2025Review
- Functional (re)annotation ofCurrent research in structural biology · 2025Article
- HadBD dehydratase from Mycobacterium tuberculosis fatty acid synthase type II: A singular structure for a unique function.Protein science : a publication of the Protein Society · 2024Article
- Mycobacterial Targets for Thiourea Derivatives: Opportunities for Virtual Screening in Tuberculosis Drug Discovery.Current medicinal chemistry · 2024Review
- Analysis of Genome-Wide Mutational Dependence in Naturally Evolving Mycobacterium tuberculosis Populations.Molecular biology and evolution · 2023Article
- 1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex inACS infectious diseases · 2022Article
- Bioassay's Directed Isolation-Structure Elucidation and Molecular Docking of Triterpenes fromEvidence-based complementary and alternative medicine : eCAM · 2022Article
- Isolation, Structure Elucidation and In Silico Prediction of Potential Drug-Like Flavonoids fromMolecules (Basel, Switzerland) · 2021Article
- (Infection and drug resistance · 2021Article
- Genetic Variation Putatively Associated withAntibiotics (Basel, Switzerland) · 2020Article
- Data on molecular docking of naturally occurring flavonoids with biologically important targets.Data in brief · 2020Article
- Mechanisms of Resistance Associated with the Inhibition of the Dehydration Step of Type II Fatty Acid Synthase inACS infectious diseases · 2020Article
- Discovery of a novel dehydratase of the fatty acid synthase type II critical for ketomycolic acid biosynthesis and virulence of Mycobacterium tuberculosis.Scientific reports · 2020Article
- Genome-wide analysis of Mycobacterium tuberculosis polymorphisms reveals lineage-specific associations with drug resistance.BMC genomics · 2019Article
- Discovery of the first macrolide antibiotic binding protein in Mycobacterium tuberculosis: a new antibiotic resistance drug target.Protein & cell · 2018Article
- HadD, a novel fatty acid synthase type II protein, is essential for alpha- and epoxy-mycolic acid biosynthesis and mycobacterial fitness.Scientific reports · 2018Article
- Deletion of a dehydratase important for intracellular growth and cording renders rough Mycobacterium abscessus avirulent.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Dehydration is one of the key steps in the biosynthesis of mycolic acids and is vital to the growth of Mycobacterium tuberculosis (Mtb). Consequently, stalling dehydration cures tuberculosis (TB). Clinically used anti-TB drugs like thiacetazone (TAC) and isoxyl (ISO) as well as flavonoids inhibit the enzyme activity of the β-hydroxyacyl-ACP dehydratase HadAB complex. How this inhibition is exerted, has remained an enigma for years. Here, we describe the first crystal structures of the MtbHadAB complex bound with flavonoid inhibitor butein, 2',4,4'-trihydroxychalcone or fisetin. Despite sharing no sequence identity from Blast, HadA and HadB adopt a very similar hotdog fold. HadA forms a tight dimer with HadB in which the proteins are sitting side-by-side, but are oriented anti-parallel. While HadB contributes the catalytically critical His-Asp dyad, HadA binds the fatty acid substrate in a long channel. The atypical double hotdog fold with a single active site formed by MtbHadAB gives rise to a long, narrow cavity that vertically traverses the fatty acid binding channel. At the base of this cavity lies Cys61, which upon mutation to Ser confers drug-resistance in TB patients. We show that inhibitors bind in this cavity and protrude into the substrate binding channel. Thus, inhibitors of MtbHadAB exert their effect by occluding substrate from the active site. The unveiling of this mechanism of inhibition paves the way for accelerating development of next generation of anti-TB drugs.
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