3PA8

Structure of the C. difficile TcdB cysteine protease domain in complex with a peptide inhibitor

Summary for 3PA8

• Entry DOI: 10.2210/pdb3pa8/pdb
• Related PRD ID: PRD_000971
• Descriptor: Toxin B, N-acetylglycyl-N-[(3S)-1-hydroxy-5-methyl-2-oxohexan-3-yl]-L-serinamide, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: clan cd cysteine protease, protease, toxin, toxin-peptide inhibitor complex, toxin/peptide inhibitor
• Biological source: Clostridium difficile
• Total number of polymer chains: 2
• Total formula weight: 59877.68

Authors

Lupardus, P.J.,Garcia, K.C. (deposition date: 2010-10-18, release date: 2010-12-15, Last modification date: 2024-10-16)

Primary citation

Puri, A.W.,Lupardus, P.J.,Deu, E.,Albrow, V.E.,Garcia, K.C.,Bogyo, M.,Shen, A.
Rational design of inhibitors and activity-based probes targeting Clostridium difficile virulence factor TcdB.
Chem.Biol., 17:1201-1211, 2010

PubMed 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 Å. 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.

PubMed: 21095570
DOI: 10.1016/j.chembiol.2010.09.011

Experimental method

X-RAY DIFFRACTION (2 Å)