ArticleAntimicrobial agents and chemotherapy2011
Structure of the Mycobacterium tuberculosis D-alanine:D-alanine ligase, a target of the antituberculosis drug D-cycloserine.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers, 1 of them a synthesis that pooled it.
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62 citing papers in PubMed, 1 synthesis or guideline pooled it, 143 citations in OpenAlex.
- Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.American journal of respiratory and critical care medicine · 2019Guideline
- Metabolic flexibility and an unusual route for peptidoglycan muramic acid recycling in mycobacteria.The Journal of biological chemistry · 2026Article
- Catalytic loop closure governs substrate selectivity in the rhizocticin biosynthetic ligases RhiM and RhiC.The Journal of biological chemistry · 2026Article
- Metabolomics profiling reveals changes in peptidoglycan and redox metabolism between ancient and modernMicrobiology spectrum · 2026Article
- Design, Synthesis, and Antitubercular Activity of Thiolutin-Cycloserine Hybrids: Reducing Cytotoxicity.Microorganisms · 2026Article
- Key Proteins and Enzymatic Mechanisms Underlying Drug Resistance in Mycobacterium tuberculosis.Advances in experimental medicine and biology · 2026Review
- A Comprehensive Review of Genetic Mechanisms ofInfection and drug resistance · 2026Review
- New pyrazole-based derivatives targeting MmpL3 transporter in Mycobacterium tuberculosis: design, synthesis, biological evaluation and molecular docking studies.Molecular diversity · 2025Article
- Overexpression, Purification, and Biochemical Characterization of the vanC2 d-Ala-d-Ser Ligase fromACS omega · 2025Article
- Development of a Spectrophotometric Assay for the Cysteine Desulfurase fromAntibiotics (Basel, Switzerland) · 2025Article
- Therapeutic drug monitoring in tuberculosis.European journal of clinical pharmacology · 2024Review
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- Role of therapeutic drug monitoring in the treatment of multi-drug resistant tuberculosis.Journal of clinical tuberculosis and other mycobacterial diseases · 2024Article
- Molecular docking, molecular dynamics simulations and binding free energy studies of interactions between Mycobacterium tuberculosis Pks13, PknG and bioactive constituents of extremophilic bacteria.Scientific reports · 2024Article
- Antitubercular drugs: possible role of natural products acting as antituberculosis medication in overcoming drug resistance and drug-induced hepatotoxicity.Naunyn-Schmiedeberg's archives of pharmacology · 2024Review
- Identification ofInfection and drug resistance · 2024Review
- Computational Guided Drug Targets Identification against Extended-Spectrum Beta-Lactamase-Producing Multi-Drug Resistant UropathogenicBiomedicines · 2023Article
- Emerging Extracellular Molecular Targets for Innovative Pharmacological Approaches to Resistant Mtb Infection.Biomolecules · 2023Review
- Anti-Tuberculosis Mur Inhibitors: Structural Insights and the Way Ahead for Development of Novel Agents.Pharmaceuticals (Basel, Switzerland) · 2023Review
- The pathogenic mechanism of Mycobacterium tuberculosis: implication for new drug development.Molecular biomedicine · 2022Review
2 more citing papers are in PubMed but not listed here.
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5 authors at 2 institutions in 1 country.
Funding
Abstract
D-alanine:D-alanine ligase (EC 6.3.2.4; Ddl) catalyzes the ATP-driven ligation of two D-alanine (D-Ala) molecules to form the D-alanyl:D-alanine dipeptide. This molecule is a key building block in peptidoglycan biosynthesis, making Ddl an attractive target for drug development. D-Cycloserine (DCS), an analog of D-Ala and a prototype Ddl inhibitor, has shown promise for the treatment of tuberculosis. Here, we report the crystal structure of Mycobacterium tuberculosis Ddl at a resolution of 2.1 Å. This structure indicates that Ddl is a dimer and consists of three discrete domains; the ligand binding cavity is at the intersection of all three domains and conjoined by several loop regions. The M. tuberculosis apo Ddl structure shows a novel conformation that has not yet been observed in Ddl enzymes from other species. The nucleotide and D-alanine binding pockets are flexible, requiring significant structural rearrangement of the bordering regions for entry and binding of both ATP and D-Ala molecules. Solution affinity and kinetic studies showed that DCS interacts with Ddl in a manner similar to that observed for D-Ala. Each ligand binds to two binding sites that have significant differences in affinity, with the first binding site exhibiting high affinity. DCS inhibits the enzyme, with a 50% inhibitory concentration (IC(50)) of 0.37 mM under standard assay conditions, implicating a preferential and weak inhibition at the second, lower-affinity binding site. Moreover, DCS binding is tighter at higher ATP concentrations. The crystal structure illustrates potential drugable sites that may result in the development of more-effective Ddl inhibitors.
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