9daq | pdb_00009daq

Structure of E. coli dihydrofolate reductase (DHFR) in an occluded conformation and in complex with a cycloguanil derivative

spinqualitylabelsall models 9daq, resolution 2.35Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9daq is a 1 chain structure with sequence from Escherichia coli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.35Å Ligands: A1A3E Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DYR_ECOL6 Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis (By similarity). Publication Abstract from PubMed Antibiotics that operate via multiple mechanisms of action are a promising strategy to combat growing resistance. Previous studies have shown that dual action antifolates formed from a pyrroloquinazolinediamine core can inhibit the growth of bacterial pathogens without developing resistance. In this work, we expand the scope of dual action antifolates by repurposing the 2,4-diamino-1,6-dihydro-1,3,5-triazine (DADHT) cycloguanil scaffold to a variety of derivatives designed to inhibit dihydrofolate reductase (DHFR) and disrupt bacterial membranes. Dual mechanism DADHTs have activity against a variety of target pathogens, including Mycobacterium tuberculosis, Mycobacterium abscessus, and Pseudomonas aeruginosa, among other ESKAPEE organisms. Through X-ray crystallography, we confirmed engagement of the Escherichia coli DHFR target and found that some DADHTs stabilize a previously unobserved conformation of the enzyme but, broadly, bind in the occluded conformation. Using in vitro inhibition of purified E. coli and Staphylococcus aureus DHFR and disruption of E. coli membranes, we determined that alkyl substitution of dihydrotriazine at the 6-position best optimizes the DADHT's two mechanisms of action. By employing both mechanisms, the DADHT spectrum of activity was extended beyond the scope of traditional antifolates. We are optimistic that the dual mechanism approach, particularly through the action of antifolates, offers a unique means of combating hard-to-treat bacterial infections. Expanding the Landscape of Dual Action Antifolate Antibacterials through 2,4-Diamino-1,6-dihydro-1,3,5-triazines.,Georgiades JD, Berkovich DA, McKee SR, Smith AR, Sankaran B, Flentie KN, Castaneda CH, Grohmann DG, Rohatgi R, Lasky C, Mason TA, Champine JE, Miller PA, Mollmann U, Moraski GC, Franzblau SG, Miller MJ, Stallings CL, Jez JM, Hathaway BA, Wencewicz TA ACS Infect Dis. 2025 Feb 14. doi: 10.1021/acsinfecdis.4c00768. PMID:39950956 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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