9BJA
C. difficile Tcdb cysteine protease domain in complex with IP6
Summary for 9BJA
| Entry DOI | 10.2210/pdb9bja/pdb |
| Descriptor | Toxin B, INOSITOL HEXAKISPHOSPHATE (3 entities in total) |
| Functional Keywords | catalytic activity peptidase activity catalytic activity, acting on a protein toxin activity small molecule binding, toxin |
| Biological source | Clostridioides difficile |
| Total number of polymer chains | 2 |
| Total formula weight | 61049.03 |
| Authors | Veyron, S.,Cummer, R. (deposition date: 2024-04-25, release date: 2024-07-03, Last modification date: 2025-03-05) |
| Primary citation | Cummer, R.,Grosjean, F.,Bolteau, R.,Vasegh, S.E.,Veyron, S.,Keogh, L.,Trempe, J.F.,Castagner, B. Structure-Activity Relationship of Inositol Thiophosphate Analogs as Allosteric Activators of Clostridioides difficile Toxin B. J.Med.Chem., 67:16576-16597, 2024 Cited by PubMed Abstract: is a bacterium that causes life-threatening intestinal infections. Infection symptoms are mediated by a toxin secreted by the bacterium. Toxin pathogenesis is modulated by the intracellular molecule, inositol-hexakisphosphate (IP6). IP6 binds to a cysteine protease domain (CPD) on the toxin, inducing autoproteolysis, which liberates a virulence factor in the cell cytosol. We developed second-generation IP6 analogs designed to induce autoproteolysis in the gut lumen, prior to toxin uptake, circumventing pathogenesis. We synthesized a panel of thiophosphate-/sulfate-containing IP6 analogs and characterized their toxin binding affinity, autoproteolysis induction, and cation interactions. Our top candidate was soluble in extracellular cation concentrations, unlike IP6. The IP6 analogs were more negatively charged than IP6, which improved affinity and stabilization of the CPD, enhancing toxin autoproteolysis. Our data illustrate the optimization of IP6 with thiophosphate biomimetic which are more capable of inducing toxin autoproteolysis than the native ligand, warranting further studies in vivo. PubMed: 39254660DOI: 10.1021/acs.jmedchem.4c01408 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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