Crystal structure of the Mycobacterium tuberculosis VirS regulator reveals its interaction with the lead compound SMARt751.

Autor: Grosse C; Unit of Microbiology, Bioorganic and Macromolecular Chemistry, Department of Research in Drug Development, Faculty of Pharmacy, Université Libre de Bruxelles, Belgium; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France., Sigoillot M; Unit of Microbiology, Bioorganic and Macromolecular Chemistry, Department of Research in Drug Development, Faculty of Pharmacy, Université Libre de Bruxelles, Belgium., Megalizzi V; Unit of Microbiology, Bioorganic and Macromolecular Chemistry, Department of Research in Drug Development, Faculty of Pharmacy, Université Libre de Bruxelles, Belgium., Tanina A; Unit of Microbiology, Bioorganic and Macromolecular Chemistry, Department of Research in Drug Development, Faculty of Pharmacy, Université Libre de Bruxelles, Belgium., Willand N; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000 Lille, France., Baulard AR; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Center for Infection and Immunity of Lille, F-59000 Lille, France., Wintjens R; Unit of Microbiology, Bioorganic and Macromolecular Chemistry, Department of Research in Drug Development, Faculty of Pharmacy, Université Libre de Bruxelles, Belgium. Electronic address: rene.wintjens@ulb.be.
Jazyk: angličtina
Zdroj: Journal of structural biology [J Struct Biol] 2024 Jun; Vol. 216 (2), pp. 108090. Date of Electronic Publication: 2024 Mar 26.
DOI: 10.1016/j.jsb.2024.108090
Abstrakt: Ethionamide (ETO) is a prodrug that is primarily used as a second-line agent in the treatment of tuberculosis. Among the bacterial ETO activators, the monooxygenase MymA has been recently identified, and its expression is regulated by the mycobacterial regulator VirS. The discovery of VirS ligands that can enhance mymA expression and thereby increase the antimycobacterial efficacy of ETO, has led to the development of a novel therapeutic strategy against tuberculosis. This strategy involves the selection of preclinical candidates, including SMARt751. We report the first crystal structure of the AraC-like regulator VirS, in complex with SMARt751, refined at 1.69 Å resolution. Crystals were obtained via an in situ proteolysis method in the requisite presence of SMARt751. The elucidated structure corresponds to the ligand-binding domain of VirS, adopting an α/β fold with structural similarities to H-NOX domains. Within the VirS structure, SMARt751 is situated in a completely enclosed hydrophobic cavity, where it forms hydrogen bonds with Asn11 and Asn149 as well as van der Waals contacts with various hydrophobic amino acids. Comprehensive structural comparisons within the AraC family of transcriptional regulators are conducted and analyzed to figure out the effects of the SMARt751 binding on the regulatory activity of VirS.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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