8g6c

GTP Cyclohydrolase-IB with manganese

spinqualitylabelsall models 8g6c, resolution 2.82Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8g6c is a 2 chain structure with sequence from Burkholderia pseudomallei. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.82Å Ligands: EDO, MN, SNC Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GCH4_BURPS Converts GTP to 7,8-dihydroneopterin triphosphate. Publication Abstract from PubMed Burkholderia thailandensis has emerged as a nonpathogenic surrogate for Burkholderia pseudomallei, the causative agent of melioidosis, and an important Gram-negative model bacterium for studying the biosynthesis and regulation of secondary metabolism. We recently reported that subinhibitory concentrations of trimethoprim induce vast changes in both the primary and secondary metabolome of B. thailandensis. In the current work, we show that the folate biosynthetic enzyme FolE2 is permissive under standard growth conditions but essential for B. thailandensis in the presence of subinhibitory doses of trimethoprim. Reasoning that FolE2 may serve as an attractive drug target, we screened for and identified ten inhibitors, including dehydrocostus lactone (DHL), parthenolide, and beta-lapachone, all of which are innocuous individually but form a chemical-synthetic lethal combination with subinhibitory doses of trimethoprim. We show that DHL is a mechanism-based inhibitor of FolE2 and capture the structure of the covalently inhibited enzyme using X-ray crystallography. In vitro, the combination of subinhibitory trimethoprim and DHL is more potent than Bactrim, the current standard of care against melioidosis. Moreover, unlike Bactrim, this combination does not affect the growth of most commensal and beneficial gut bacteria tested, thereby providing a degree of specificity against B. pseudomallei. Our work provides a path for identifying antimicrobial drug targets and for utilizing binary combinations of molecules that form a toxic cocktail based on metabolic idiosyncrasies of specific pathogens. Combatting melioidosis with chemical synthetic lethality.,Zhang Y, McWhorter KL, Rosen PC, Klaus JR, Gallant E, Amaya Lopez CY, Jhunjhunwala R, Chandler JR, Davis KM, Seyedsayamdost MR Proc Natl Acad Sci U S A. 2024 Nov 12;121(46):e2406771121. doi: , 10.1073/pnas.2406771121. Epub 2024 Nov 4. PMID:39495920 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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