title: The X-ray structure of ricin A chain with a novel inhibitor.
abstract: Ricin is a potent heterodimeric cytotoxin; the B chain binds eucaryotic cell surfaces aiding uptake and the A chain, RTA, reaches the cytoplasm where it enzymatically depurinates a key ribosomal adenine, inhibiting protein synthesis. Ricin is known to be an agent in bioterrorist repertoires and there is great interest in finding, or creating, efficacious inhibitors of the toxin as potential antidotes. We have previously identified two families of bicyclic RTA inhibitors, pterins and purines. Both classes have poor solubility which impairs inhibitor development. Here we report the use of 2-amino-4,6-dihydroxy-pyrimidines as RTA inhibitors. Unlike previously observed single ring inhibitor platforms, these displace Tyr 80 and bind deep in the RTA specificity pocket. These compounds are at least 10 times more soluble than pterin-based inhibitors and appear to be useful new class of ricin inhibitors.
authors.affiliation: Institute for Cellular and Molecular Biology, Department of Chemistry and Biochemistry, University of Texas, Austin, 78712, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.forename: Arthur F
authors.initials: AF
authors.lastname: Monzingo
authors.forename: Jon D
authors.initials: JD
authors.lastname: Robertus
mesh_terms: D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D012276:Ricin / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D011743:Pyrimidines; D012276:Ricin