4CAV

Crystal structure of Aspergillus fumigatus N-myristoyl transferase in complex with myristoyl CoA and a benzofuran ligand R0-09-4879

4CAV の概要

• エントリーDOI: 10.2210/pdb4cav/pdb
• 関連するPDBエントリー: 4CAW 4CAX
• 分子名称: GLYCYLPEPTIDE N-TETRADECANOYLTRANSFERASE, CHLORIDE ION, 3-[[3-methyl-2-[[2,3,4-tris(fluoranyl)phenoxy]methyl]-1-benzofuran-4-yl]oxy]-N-(pyridin-3-ylmethyl)propan-1-amine, ... (5 entities in total)
• 機能のキーワード: transferase, drug discovery
• 由来する生物種: ASPERGILLUS FUMIGATUS
• 細胞内の位置: Cytoplasm: Q9UVX3
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 48913.05

構造登録者

Robinson, D.A.,Fang, W.,Raimi, O.G.,Blair, D.E.,Harrison, J.,Ruda, G.F.,Lockhart, D.E.A.,Torrie, L.S.,Wyatt, P.G.,Gilbert, I.H.,Van Aalten, D.M.F. (登録日: 2013-10-09, 公開日: 2014-09-17, 最終更新日: 2023-12-20)

主引用文献

Fang, W.,Robinson, D.A.,Raimi, O.G.,Blair, D.E.,Harrison, J.R.,Lockhart, D.E.A.,Torrie, L.S.,Ruda, G.F.,Wyatt, P.G.,Gilbert, I.H.,Van Aalten, D.M.F.
N-Myristoyltransferase is a Cell Wall Target in Aspergillus Fumigatus.
Acs Chem.Biol., 10:1425-, 2015

PubMed Abstract: Treatment of filamentous fungal infections relies on a limited repertoire of antifungal agents. Compounds possessing novel modes of action are urgently required. N-myristoylation is a ubiquitous modification of eukaryotic proteins. The enzyme N-myristoyltransferase (NMT) has been considered a potential therapeutic target in protozoa and yeasts. Here, we show that the filamentous fungal pathogen Aspergillus fumigatus possesses an active NMT enzyme that is essential for survival. Surprisingly, partial repression of the gene revealed downstream effects of N-myristoylation on cell wall morphology. Screening a library of inhibitors led to the discovery of a pyrazole sulphonamide compound that inhibits the enzyme and is fungicidal under partially repressive nmt conditions. Together with a crystallographic complex showing the inhibitor binding in the peptide substrate pocket, we provide evidence of NMT being a potential drug target in A. fumigatus.

PubMed: 25706802
DOI: 10.1021/CB5008647

実験手法

X-RAY DIFFRACTION (1.89 Å)