STRUCTURE-BASED IDENTIFICATION OF A RICIN INHIBITOR

Ricin is a potent cytotoxin which has been used widely in the construc tion of therapeutic agents such as immunotoxins. Recently it has been used by governments and underground groups as a poison. There is inter est in identifying and designing effective inhibitors of the ricin A c hain (RTA). In this study computer-assisted searches indicated that pt erins might bind in the RTA active site which normally recognizes a sp ecific adenine base on rRNA. Kinetic assays showed that pteroic acid c ould inhibit RTA activity with an apparent K-i of 0.6 mM. A 2.3 Angstr om crystal structure of the complex revealed the mode of binding. The pterin ring displaces Tyr80 and binds in the adenine pocket making spe cific hydrogen bonds to active site residues. The benzoate moiety of p teroic acid binds on the opposite side of Tyr80 making van der Waals c ontact with the Tyr ring and forming a hydrogen bond with Asn78. Neopt erin, a propane triol derivative of pterin, also binds to RTA as revea led by the X-ray structure of its complex with RTA. Neither pterin-6-c arboxylic acid nor folic acid bind to the crystal or act as inhibitors . The models observed suggest alterations to the pterin moiety which m ay produce more potent and specific RTA inhibitors. (C) 1997 Academic Press Limited.