1PWP

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

Summary for 1PWP

• Entry DOI: 10.2210/pdb1pwp/pdb
• Related: 1PWQ
• Descriptor: Lethal factor, ZINC ION, N,N'-BIS(4-AMINO-2-METHYLQUINOLIN-6-YL)UREA (3 entities in total)
• Functional Keywords: anthrax toxin, lethal factor, small molecule inhibitor, hydrolase
• Biological source: Bacillus anthracis
• Cellular location: Secreted: P15917
• Total number of polymer chains: 2
• Total formula weight: 181589.29

Authors

Wong, T.Y.,Schwarzenbacher, R.,Liddington, R.C. (deposition date: 2003-07-02, release date: 2004-01-13, Last modification date: 2023-08-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.9 Å)