Rational Design of Femtomolar Inhibitors of Isoleucyl tRNA Synthetase from a Binding Model for Pseudomonic Acid-A
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- 作者：Murray J. B. Brown ; Lucy M. Mensah ; Michael L. Doyle ; Nigel J. P. Broom ; Neal Osbourne ; Andrew K. Forrest ; Christine M. Richardson ; Peter J. O'Hanlon ; and Andrew J. Pope
- 刊名：Biochemistry
- 出版年：2000
- 出版时间：May 23, 2000
- 年：2000
- 卷：39
- 期：20
- 页码：6003 - 6011
- 全文大小：569K
- 年卷期：v.39,no.20(May 23, 2000)
- ISSN：1520-4995
文摘
This paper describes the design and characterization of novel inhibitors of IleRS, whose bindingaffinity approaches the tightest reported for noncovalent inhibition. Compounds were designed from abinding model for the natural product pseudomonic acid-A (PS-A) together with a detailed understandingof the reaction cycle of IleRS and characterization of the mode of binding of the reaction intermediateIleAMP. The interactions of the compounds with IleRS were characterized by inhibition of aminoacylationof tRNA or PPi/ATP exchange at supersaturating substrate concentration and by transient kinetics andcalorimetry methods. A detailed understanding of the interaction of a comprehensive series of compoundswith IleRS allowed the identification of key features and hence the design of exquisitely potent inhibitors.Predictions based on these results have been recently supported by a docking model based on the crystalstructure of IleRS with PS-A [Silvian, L. F., Wang J. M., and Steitz T. A. (1999) Science 285 1074-1077].