6TDF

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

6TDF の概要

• エントリーDOI: 10.2210/pdb6tdf/pdb
• 分子名称: 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)
• 機能のキーワード: fragment screening, anti fungal, aspergillus fumigatus, inhibitor, transferase
• 由来する生物種: Aspergillus fumigatus Af293
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22512.99

構造登録者

Raimi, O.G.,Stanley, M.,Lockhart, D. (登録日: 2019-11-08, 公開日: 2020-04-29, 最終更新日: 2024-01-24)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.01 Å)