Further Insight into Crystal Structures of Escherichia coli IspH/LytB in Complex with Two Potent Inhibitors of the MEP Pathway: A Starting Point for Rational Design of New Antimicrobials |
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| Authors: | Dr Franck Borel Elodie Barbier Dr Sergiy Krasutsky Dr Karnjapan Janthawornpong Dr Philippe Chaignon Dr C Dale Poulter Dr Jean-Luc Ferrer Dr Myriam Seemann |
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| Affiliation: | 1. Institut de Biologie Structurale IBS, Université Grenoble Alpes, CEA, CNRS, 38044 Grenoble, France;2. Department of Chemistry, University of Utah, 315 South 1400 East RM 2020, Salt Lake City, UT, 84112 USA;3. Université de Strasbourg, CNRS, Institut de Chimie UMR 7177, Chim Biol&Appl Therap, 4, rue Blaise Pascal, 67070 Strasbourg, France |
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| Abstract: | IspH, also called LytB, a protein involved in the biosynthesis of isoprenoids through the methylerythritol phosphate pathway, is an attractive target for the development of new antimicrobial drugs. Here, we report crystal structures of Escherichia coli IspH in complex with the two most potent inhibitors: (E)-4-mercapto-3-methylbut-2-en-1-yl diphosphate (TMBPP) and (E)-4-amino-3-methylbut-2-en-1-yl diphosphate (AMBPP) at 1.95 and 1.7 Å resolution, respectively. The structure of the E. coli IspH:TMBPP complex exhibited two conformers of the inhibitor. This unexpected feature was exploited to design and evolve new antimicrobial candidates in silico. |
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| Keywords: | [4Fe-4S] cluster In silico docking LytB/IspH MEP pathway inhibitors X-ray crystallography |
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