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Exploration of the S'1 subsite of neprilysin: a joined molecular modeling and site-directed mutagenesis study.

Abstract : Based on the recently described three-dimensional model of the 507-749 region of neprilysin, which contains the catalytic site of the enzyme, experiments were performed to improve the proposed topology of its large and hydrophobic S(')(1) subsite. Docking studies, site-directed mutagenesis, and biochemical studies were combined. The mutations of various residues proposed to be part of the S(')(1) subsite (F563A, F564A, M579A, F716A, and I718A) did not induce major structural reorganization of the active site as demonstrated by the slight modification of the enzyme activity. The mutations were also analyzed by measuring the inhibitory potencies of thiol inhibitors containing P(')(1) moieties of increasing sizes. These results combined with molecular modeling studies support the proposed topology of the S(')(1) subsite. This, and the critical role of F563 and M579 in inhibitor binding, could facilitate the synthesis of new potent and selective inhibitors.
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https://www.hal.inserm.fr/inserm-00171018
Contributor : Cynthia Marie-Claire <>
Submitted on : Tuesday, September 11, 2007 - 11:45:14 AM
Last modification on : Tuesday, September 22, 2020 - 3:59:02 AM
Long-term archiving on: : Friday, November 25, 2016 - 4:53:19 PM

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  • HAL Id : inserm-00171018, version 1
  • PUBMED : 10813818

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Cynthia Marie-Claire, Gilles Tiraboschi, Emmanuel Ruffet, Nicolas Inguimbert, Marie-Claude Fournie-Zaluski, et al.. Exploration of the S'1 subsite of neprilysin: a joined molecular modeling and site-directed mutagenesis study.. Proteins - Structure, Function and Bioinformatics, Wiley, 2000, 39 (4), pp.365-71. ⟨inserm-00171018⟩

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