1PWP

Crystal Structure of the Anthrax Lethal Factor complexed with Small Molecule Inhibitor NSC 12155

1PWP の概要

• エントリーDOI: 10.2210/pdb1pwp/pdb
• 関連するPDBエントリー: 1PWQ
• 分子名称: Lethal factor, ZINC ION, N,N'-BIS(4-AMINO-2-METHYLQUINOLIN-6-YL)UREA (3 entities in total)
• 機能のキーワード: anthrax toxin, lethal factor, small molecule inhibitor, hydrolase
• 由来する生物種: Bacillus anthracis
• 細胞内の位置: Secreted: P15917
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 181589.29

構造登録者

Wong, T.Y.,Schwarzenbacher, R.,Liddington, R.C. (登録日: 2003-07-02, 公開日: 2004-01-13, 最終更新日: 2023-08-16)

主引用文献

Panchal, R.G.,Hermone, A.R.,Nguyen, T.L.,Wong, T.Y.,Schwarzenbacher, R.,Schmidt, J.,Lane, D.,McGrath, C.,Turk, B.E.,Burnett, J.,Aman, M.J.,Little, S.,Sausville, E.A.,Zaharevitz, D.W.,Cantley, L.C.,Liddington, R.C.,Gussio, R.,Bavari, S.
Identification of small molecule inhibitors of anthrax lethal factor.
Nat.Struct.Mol.Biol., 11:67-72, 2004

PubMed Abstract: The virulent spore-forming bacterium Bacillus anthracis secretes anthrax toxin composed of protective antigen (PA), lethal factor (LF) and edema factor (EF). LF is a Zn-dependent metalloprotease that inactivates key signaling molecules, such as mitogen-activated protein kinase kinases (MAPKK), to ultimately cause cell death. We report here the identification of small molecule (nonpeptidic) inhibitors of LF. Using a two-stage screening assay, we determined the LF inhibitory properties of 19 compounds. Here, we describe six inhibitors on the basis of a pharmacophoric relationship determined using X-ray crystallographic data, molecular docking studies and three-dimensional (3D) database mining from the US National Cancer Institute (NCI) chemical repository. Three of these compounds have K(i) values in the 0.5-5 microM range and show competitive inhibition. These molecular scaffolds may be used to develop therapeutically viable inhibitors of LF.

PubMed: 14718925
DOI: 10.1038/nsmb711

実験手法

X-RAY DIFFRACTION (2.9 Å)