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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.
Chembiochem. 2017 11 02; 18(21):2137-2144.C

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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Publisher Full Text (DOI)

Authors+Show Affiliations

Borel F
Institut de Biologie Structurale IBS, Université Grenoble Alpes, CEA, CNRS, 38044, Grenoble, France.
Barbier E
Institut de Biologie Structurale IBS, Université Grenoble Alpes, CEA, CNRS, 38044, Grenoble, France.
Krasutsky S
Department of Chemistry, University of Utah, 315 South 1400 East RM 2020, Salt Lake City, UT, 84112, USA.
Janthawornpong K
Université de Strasbourg, CNRS, Institut de Chimie UMR 7177, Chim Biol&Appl Therap, 4, rue Blaise Pascal, 67070, Strasbourg, France.
Chaignon P
Université de Strasbourg, CNRS, Institut de Chimie UMR 7177, Chim Biol&Appl Therap, 4, rue Blaise Pascal, 67070, Strasbourg, France.
Poulter CD
Department of Chemistry, University of Utah, 315 South 1400 East RM 2020, Salt Lake City, UT, 84112, USA.
Ferrer JL
Institut de Biologie Structurale IBS, Université Grenoble Alpes, CEA, CNRS, 38044, Grenoble, France.
Seemann M
Université de Strasbourg, CNRS, Institut de Chimie UMR 7177, Chim Biol&Appl Therap, 4, rue Blaise Pascal, 67070, Strasbourg, France.

MeSH

Anti-Bacterial AgentsCrystallography, X-RayDrug DesignEnzyme InhibitorsErythritolEscherichia coliEscherichia coli ProteinsMolecular Docking SimulationMolecular StructureOxidoreductasesSugar Phosphates

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28862365

Citation

Borel, Franck, et al. "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." Chembiochem : a European Journal of Chemical Biology, vol. 18, no. 21, 2017, pp. 2137-2144.
Borel F, Barbier E, Krasutsky S, et al. 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. Chembiochem. 2017;18(21):2137-2144.
Borel, F., Barbier, E., Krasutsky, S., Janthawornpong, K., Chaignon, P., Poulter, C. D., Ferrer, J. L., & Seemann, M. (2017). 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. Chembiochem : a European Journal of Chemical Biology, 18(21), 2137-2144. https://doi.org/10.1002/cbic.201700363
Borel F, et al. 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. Chembiochem. 2017 11 2;18(21):2137-2144. PubMed PMID: 28862365.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Borel,Franck, AU - Barbier,Elodie, AU - Krasutsky,Sergiy, AU - Janthawornpong,Karnjapan, AU - Chaignon,Philippe, AU - Poulter,C Dale, AU - Ferrer,Jean-Luc, AU - Seemann,Myriam, Y1 - 2017/10/02/ PY - 2017/07/06/received PY - 2017/9/2/pubmed PY - 2017/11/29/medline PY - 2017/9/2/entrez KW - In silico docking KW - LytB/IspH KW - MEP pathway inhibitors KW - X-ray crystallography KW - [4Fe-4S] cluster SP - 2137 EP - 2144 JF - Chembiochem : a European journal of chemical biology JO - Chembiochem VL - 18 IS - 21 N2 - 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. SN - 1439-7633 UR - https://www.unboundmedicine.com/medline/citation/28862365/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_ L2 - https://doi.org/10.1002/cbic.201700363 DB - PRIME DP - Unbound Medicine ER -