3PA8: Structure Of The C. Difficile Tcdb Cysteine Protease Domain In Complex With A Peptide Inhibitor

Citation:
Abstract
Clostridium difficile is a leading cause of nosocomial infections. The major virulence factors of this pathogen are the multi-domain toxins TcdA and TcdB. These toxins contain a cysteine protease domain (CPD) that autoproteolytically releases a cytotoxic effector domain upon binding intracellular inositol hexakisphosphate. Currently, there are no known inhibitors of this protease. Here, we describe the rational design of covalent small molecule inhibitors of TcdB CPD. We identified compounds that inactivate TcdB holotoxin function in cells and solved the structure of inhibitor-bound protease to 2.0 A. This structure reveals the molecular basis of CPD substrate recognition and informed the synthesis of activity-based probes for this enzyme. The inhibitors presented will guide the development of therapeutics targeting C. difficile, and the probes will serve as tools for studying the unique activation mechanism of bacterial toxin CPDs.
PDB ID: 3PA8Download
MMDB ID: 87378
PDB Deposition Date: 2010/10/18
Updated in MMDB: 2010/12
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Similar Structures:
Biological Unit for 3PA8: dimeric; determined by author and by software (PISA)
Molecular Components in 3PA8
Label Count Molecule
Proteins (2 molecules)
2
Toxin B
Molecule annotation
Chemicals (7 molecules)
1
2
2
1
3
2
4
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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