Identification and structural analysis of ricin inhibitors. Final report
Ricin is a potent cytotoxin which has been used by governments and terrorists as a poison. The three-dimensional structure of this toxic molecule was solved by X-ray crystallography, including an atomic description of its active site. The goal of this project was to use computer searches and other molecular modeling techniques to identify an inhibitor or ricin A chain (RTA). The program CHEM-X was used to predict that pteroic acid (PTA) would bind to RTA. This was shown to be the case by kinetic assays, where PTA protected ribosomes against the action of RTA, and by X-ray crystallography. The affinity of PTA is weak, with a Ki estimated at 600 Micrometers. The pterin group of PTA was observed to make many polar interactions with RTA within the specificity site of the enzyme, and to bind more strongly than the natural substrate adenine. Further work will be required to increase the binding affinity of this class of inhibitors, and to improve their solubility if efficacious antidotes are to be designed from this lead.
- Research Organization:
- Univ. of Texas, Austin, TX (United States)
- OSTI ID:
- 481285
- Report Number(s):
- AD-A-322174/4/XAB; CNN: Contract DAMD17-94-C-4006; TRN: 71340297
- Resource Relation:
- Other Information: PBD: Dec 1996
- Country of Publication:
- United States
- Language:
- English
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