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Mechanistic and structural insights into the proteolytic activation of Vibrio cholerae MARTX toxin.
- Source :
-
Nature chemical biology [Nat Chem Biol] 2009 Jul; Vol. 5 (7), pp. 469-78. - Publication Year :
- 2009
-
Abstract
- MARTX toxins modulate the virulence of a number of Gram-negative Vibrio species. This family of toxins is defined by the presence of a cysteine protease domain (CPD), which proteolytically activates the Vibrio cholerae MARTX toxin. Although recent structural studies of the CPD have uncovered a new allosteric activation mechanism, the mechanism of CPD substrate recognition or toxin processing is unknown. Here we show that interdomain cleavage of MARTXVc enhances effector domain function. We also identify the first small-molecule inhibitors of this protease domain and present the 2.35-A structure of the CPD bound to one of these inhibitors. This structure, coupled with biochemical and mutational studies of the toxin, reveals the molecular basis of CPD substrate specificity and underscores the evolutionary relationship between the CPD and the clan CD caspase proteases. These studies are likely to prove valuable for devising new antitoxin strategies for a number of bacterial pathogens.
- Subjects :
- Allosteric Regulation
Amino Acid Sequence
Blotting, Western
Catalytic Domain
Crystallography, X-Ray
Enzyme Activation drug effects
Models, Molecular
Molecular Sequence Data
Protein Binding
Protein Structure, Secondary
Sequence Alignment
Spectroscopy, Fourier Transform Infrared
Substrate Specificity
Vibrio cholerae drug effects
Vibrio cholerae enzymology
Cholera Toxin chemistry
Cholera Toxin metabolism
Cysteine Proteases metabolism
Cysteine Proteinase Inhibitors pharmacology
Vibrio cholerae metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4469
- Volume :
- 5
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Nature chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 19465933
- Full Text :
- https://doi.org/10.1038/nchembio.178