First-in-class allosteric inhibitors of bacterial IMPDHs
| Autor: | Gilles Labesse, Olivier Helynck, Sophie Vichier-Guerre, Thomas Alexandre, Muriel Gelin, Hélène Munier-Lehmann, Alexandru Lupan, Laurence Dugué, Ahmed Haouz |
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| Přispěvatelé: | Université Sorbonne Paris Cité (USPC), Chimie et Biocatalyse, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Biochimie Structurale [Montpellier] (CBS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cristallographie (Plateforme) - Crystallography (Platform), This work was supported in part by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé Et de la Recherche Médicale (INSERM), the Institut Pasteur, the Conseil Régional d'Ile-de-France (Chemical Library Project, grants n° I 06-222/R and I 09-1739/R, which included a postdoctoral fellowship for Alexandru Lupan) and the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INBS-05.Thomas Alexandre was a recipient of a PhD fellowship from the Conseil Régional d'Ile-de-France and the 'D.I.M. maladies infectieuses, parasitaires et nosocomiales émergentes' 2011., We thank Emilie Dufour for participation in the chemical library screening, Zakaria Jemouai for participation in the kinetic characterization of the allosteric inhibitors and Aurélie Bourderioux for performing the fluorescence experiments. We thank the Molecular Biophysics facility (PFBMI, Institut Pasteur, Paris) for their technical assistance and helpful suggestions. The authors are grateful to the staff of the Crystallographic platform from the Institut Pasteur for robot-driven crystallization screening. We thank Alexandre Chenal for fruitful discussion and technical assistance for fluorescence experiments, and Thomas J. Dougherty for careful reading of this manuscript. We acknowledge the Synchrotron SOLEIL (St Aubin, France) staff for assistance and advice during data collection on PROXIMA-1 (X-ray diffraction data) and SWING (SAXS data) beamlines., ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), Munier-Lehmann, Hélène, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Cristallographie (Plate-forme) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
MESH: IMP Dehydrogenase
Drug target Dehydrogenase [CHIM.THER]Chemical Sciences/Medicinal Chemistry 01 natural sciences Nucleotide metabolism MESH: Allosteric Regulation IMPDH MESH: Apoproteins Low affinity Adenosine Triphosphate IMP Dehydrogenase Drug Discovery MESH: Adenosine Triphosphate Enzyme Inhibitors MESH: Bacterial Proteins ComputingMilieux_MISCELLANEOUS chemistry.chemical_classification 0303 health sciences Effector [CHIM.ORGA]Chemical Sciences/Organic chemistry General Medicine Bateman domain [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] Biochemistry MESH: Enzyme Inhibitors MESH: Protein Domains Allosteric inhibitor [CHIM.THER] Chemical Sciences/Medicinal Chemistry Allosteric regulation Chemical library screening Small Molecule Libraries 03 medical and health sciences Allosteric Regulation Bacterial Proteins Protein Domains Oxidoreductase MESH: Small Molecule Libraries [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology Quaternary structure [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology 030304 developmental biology Pharmacology 010405 organic chemistry Organic Chemistry [CHIM.ORGA] Chemical Sciences/Organic chemistry [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology 0104 chemical sciences Enzyme chemistry Protein quaternary structure [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology Apoproteins |
| Zdroj: | European Journal of Medicinal Chemistry European Journal of Medicinal Chemistry, 2019, 167, pp.124-132. ⟨10.1016/j.ejmech.2019.01.064⟩ European Journal of Medicinal Chemistry, Elsevier, 2019, 167, pp.124-132. ⟨10.1016/j.ejmech.2019.01.064⟩ |
| ISSN: | 0223-5234 1768-3254 |
| DOI: | 10.1016/j.ejmech.2019.01.064⟩ |
| Popis: | International audience; Inosine-5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme in many bacterial pathogens and is considered as a potential drug target for the development of new antibacterial agents. Our recent work has revealed the crucial role of one of the two structural domains (i.e. Bateman domain) in the regulation of the quaternary structure and enzymatic activity of bacterial IMPDHs. Thus, we have screened chemical libraries to search for compounds targeting the Bateman domain and identified first in-class allosteric inhibitors of a bacterial IMPDH. These inhibitors were shown to counteract the activation by the natural positive effector, MgATP, and to block the enzyme in its apo conformation (low affinity for IMP). Our structural studies demonstrate the versatility of the Bateman domain to accommodate totally unrelated chemical scaffolds and pave the way for the development of allosteric inhibitors, an avenue little explored until now. |
| Databáze: | OpenAIRE |
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