1ZXV

X-Ray Crystal Structure of the Anthrax Lethal Factor Bound to a Small Molecule Inhibitor, BI-MFM3, 3-{5-[5-(4-Chloro-phenyl)-furan-2-ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionic acid.

Summary for 1ZXV

• Entry DOI: 10.2210/pdb1zxv/pdb
• Descriptor: lethal factor, ZINC ION, (E)-3-(5((5-(4-CHLOROPHENYL)FURAN-2-YL)METHYLENE)-4-OXO-2-THIOXOTHIAZOLIDIN-3-YL)PROPANOIC ACID (3 entities in total)
• Functional Keywords: anthrax toxin lethal factor, protein and small molecule inhibitor complex, zinc metalloproteinase, hydrolase
• Biological source: Bacillus anthracis
• Total number of polymer chains: 2
• Total formula weight: 181632.17

Authors

Wong, T.Y.,Liddington, R.C. (deposition date: 2005-06-08, release date: 2005-07-05, Last modification date: 2024-03-13)

Primary citation

Forino, M.,Johnson, S.,Wong, T.Y.,Rozanov, D.V.,Savinov, A.Y.,Li, W.,Fattorusso, R.,Becattini, B.,Orry, A.J.,Jung, D.,Abagyan, R.A.,Smith, J.W.,Alibek, K.,Liddington, R.C.,Strongin, A.Y.,Pellecchia, M.
Efficient synthetic inhibitors of anthrax lethal factor.
Proc.Natl.Acad.Sci.Usa, 102:9499-9504, 2005

PubMed Abstract: Inhalation anthrax is a deadly disease for which there is currently no effective treatment. Bacillus anthracis lethal factor (LF) metalloproteinase is an integral component of the tripartite anthrax lethal toxin that is essential for the onset and progression of anthrax. We report here on a fragment-based approach that allowed us to develop inhibitors of LF. The small-molecule inhibitors we have designed, synthesized, and tested are highly potent and selective against LF in both in vitro tests and cell-based assays. These inhibitors do not affect the prototype human metalloproteinases that are structurally similar to LF. Initial in vivo evaluation of postexposure efficacy of our inhibitors combined with antibiotic ciprofloxacin against B. anthracis resulted in significant protection. Our data strongly indicate that the scaffold of inhibitors we have identified is the foundation for the development of novel, safe, and effective emergency therapy of postexposure inhalation anthrax.

PubMed: 15983377
DOI: 10.1073/pnas.0502733102

Experimental method

X-RAY DIFFRACTION (2.67 Å)