6TDF

Crystal structure of Aspergillus fumigatus Glucosamine-6-phosphate N-acetyltransferase 1 in complex with compound 3

Summary for 6TDF

• Entry DOI: 10.2210/pdb6tdf/pdb
• Descriptor: Glucosamine 6-phosphate N-acetyltransferase, ACETYL COENZYME *A, 2-[[3,5-bis(chloranyl)-4-(4~{H}-1,2,4-triazol-3-yl)phenyl]-(2-hydroxyethyl)amino]ethanol, ... (5 entities in total)
• Functional Keywords: fragment screening, anti fungal, aspergillus fumigatus, inhibitor, transferase
• Biological source: Aspergillus fumigatus Af293
• Total number of polymer chains: 1
• Total formula weight: 22512.99

Authors

Raimi, O.G.,Stanley, M.,Lockhart, D. (deposition date: 2019-11-08, release date: 2020-04-29, Last modification date: 2024-01-24)

Primary citation

Lockhart, D.E.A.,Stanley, M.,Raimi, O.G.,Robinson, D.A.,Boldovjakova, D.,Squair, D.R.,Ferenbach, A.T.,Fang, W.,van Aalten, D.M.F.
Targeting a critical step in fungal hexosamine biosynthesis.
J.Biol.Chem., 295:8678-8691, 2020

PubMed Abstract: is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment including host defenses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. As 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 -acetyltransferase (Gna1), a key enzyme in this pathway, is an exploitable antifungal drug target. 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 Δ 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 submicromolar binder. Taken together, we have provided genetic, structural, and chemical evidence that Gna1 is an antifungal target in .

PubMed: 32341126
DOI: 10.1074/jbc.RA120.012985

Experimental method

X-RAY DIFFRACTION (2.01 Å)