6tdh

Crystal structure of Aspergillus fumigatus Glucosamine-6-phosphate N-acetyltransferase 1 in complex with compound 1

spinqualitylabelsall models 6tdh, resolution 1.58Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6tdh is a 1 chain structure with sequence from Aspergillus fumigatus Af293. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.58Å Ligands: ACO, N2Z Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q4WCU5_ASPFU Publication Abstract from PubMed Aspergillus fumigatus is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment, including host defense responses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. Because this pathway is critical for fungal cell wall integrity, the hexosamine biosynthesis enzymes represent potential targets of antifungal drugs. Here, we provide genetic and chemical evidence that glucosamine 6-phosphate N-acetyltransferase (Gna1), a key enzyme in this pathway, is an exploitable antifungal drug target. GNA1 deletion resulted in loss of fungal viability and disruption of the cell wall, phenotypes that could be rescued by exogenous GlcNAc, the product of the Gna1 enzyme. In a murine model of aspergillosis, the Deltagna1 mutant strain exhibited attenuated virulence. Using a fragment-based approach, we discovered a small heterocyclic scaffold that binds proximal to the Gna1 active site and can be optimized to a selective sub-micromolar binder. Taken together, we have provided genetic, structural, and chemical evidence that Gna1 is an antifungal target in A. fumigatus. Targeting a critical step in fungal hexosamine biosynthesis.,Lockhart DEA, Stanley M, Raimi OG, Robinson DA, Boldovjakova D, Squair DR, Ferenbach AT, Fang W, van Aalten DMF J Biol Chem. 2020 Apr 27. pii: RA120.012985. doi: 10.1074/jbc.RA120.012985. PMID:32341126 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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