6nnc | pdb_00006nnc

Structure of Dihydrofolate reductase from Mycobacterium tuberculosis in complex with NADPH and pemetrexed

spinqualitylabelsall models 6nnc, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6nnc is a 2 chain structure with sequence from Myctu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CO, LYA, NDP, SO4 Gene: folA, dfrA, Rv2763c, MTV002.28c (MYCTU) Activity: Dihydrofolate reductase, with EC number 1.5.1.3 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [DYR_MYCTU] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Publication Abstract from PubMed Tuberculosis is a disease caused by Mycobacterium tuberculosis and is the leading cause of death from a single infectious pathogen, with a high prevalence in developing countries in Africa and Asia. There still is a need for the development or repurposing of novel therapies to combat this disease owing to the long-term nature of current therapies and because of the number of reported resistant strains. Here, structures of dihydrofolate reductase from M. tuberculosis (MtDHFR), which is a key target of the folate pathway, are reported in complex with four antifolates, pyrimethamine, cycloguanil, diaverdine and pemetrexed, and its substrate dihydrofolate in order to understand their binding modes. The structures of all of these complexes were obtained in the closed-conformation state of the enzyme and a fine structural analysis indicated motion in key regions of the substrate-binding site and different binding modes of the ligands. In addition, the affinities, through Kd measurement, of diaverdine and methotrexate have been determined; MtDHFR has a lower affinity (highest Kd) for diaverdine than pyrimethamine and trimethoprim, and a very high affinity for methotrexate, as expected. The structural comparisons and analysis described in this work provide new information about the plasticity of MtDHFR and the binding effects of different antifolates. Crystal structures of the closed form of Mycobacterium tuberculosis dihydrofolate reductase in complex with dihydrofolate and antifolates.,Ribeiro JA, Chavez-Pacheco SM, de Oliveira GS, Silva CDS, Giudice JHP, Libreros-Zuniga GA, Dias MVB Acta Crystallogr D Struct Biol. 2019 Jul 1;75(Pt 7):682-693. doi:, 10.1107/S205979831900901X. Epub 2019 Jul 4. PMID:31282477 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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