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Structure-based identification of a ricin inhibitor.

Abstract：

:Ricin is a potent cytotoxin which has been used widely in the construction of therapeutic agents such as immunotoxins. Recently it has been used by governments and underground groups as a poison. There is interest in identifying and designing effective inhibitors of the ricin A chain (RTA). In this study computer-assisted searches indicated that pterins might bind in the RTA active site which normally recognizes a specific adenine base on rRNA. Kinetic assays showed that pteroic acid could inhibit RTA activity with an apparent Ki of 0.6 mM. A 2.3 A crystal structure of the complex revealed the mode of binding. The pterin ring displaces Tyr80 and binds in the adenine pocket making specific hydrogen bonds to active site residues. The benzoate moiety of pteroic acid binds on the opposite side of Tyr80 making van der Waals contact with the Tyr ring and forming a hydrogen bond with Asn78. Neopterin, a propane triol derivative of pterin, also binds to RTA as revealed by the X-ray structure of its complex with RTA. Neither pterin-6-carboxylic acid nor folic acid bind to the crystal or act as inhibitors. The models observed suggest alterations to the pterin moiety which may produce more potent and specific RTA inhibitors.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Yan X,Hollis T,Svinth M,Day P,Monzingo AF,Milne GW,Robertus JD

doi

10.1006/jmbi.1996.0865

subject

Has Abstract

pub_date

1997-03-14 00:00:00

pages

1043-9

issue

5

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(96)90865-7

journal_volume

266

pub_type

杂志文章

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