Structural Study of a New MbtI-Inhibitor Complex: Towards an Optimized Model for Structure-Based Drug Discovery
MbtI from <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) is a Mg<sup>2+</sup>-dependent salicylate synthase, belonging to the chorismate-utilizing enzyme (CUE) family. As a fundamental player in iron acquisition, MbtI promotes the survival and pathogenicity of <...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/11/1559 |
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| author | Matteo Mori Stefania Villa Laurent R. Chiarelli Fiorella Meneghetti Marco Bellinzoni |
| author_facet | Matteo Mori Stefania Villa Laurent R. Chiarelli Fiorella Meneghetti Marco Bellinzoni |
| author_sort | Matteo Mori |
| collection | DOAJ |
| description | MbtI from <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) is a Mg<sup>2+</sup>-dependent salicylate synthase, belonging to the chorismate-utilizing enzyme (CUE) family. As a fundamental player in iron acquisition, MbtI promotes the survival and pathogenicity of <i>Mtb</i> in the infected host. Hence, it has emerged in the last decade as an innovative, potential target for the anti-virulence therapy of tuberculosis. In this context, 5-phenylfuran-2-carboxylic acids have been identified as potent MbtI inhibitors. The first co-crystal structure of MbtI in complex with a member of this class was described in 2020, showing the enzyme adopting an open configuration. Due to the high mobility of the loop adjacent to the binding pocket, large portions of the amino acid chain were not defined in the electron density map, hindering computational efforts aimed at structure-driven ligand optimization. Herein, we report a new, high-resolution co-crystal structure of MbtI with a furan-based derivative, in which the closed configuration of the enzyme allowed tracing the entirety of the active site pocket in the presence of the bound inhibitor. Moreover, we describe a new crystal structure of MbtI in open conformation and in complex with the known inhibitor methyl-AMT, suggesting that in vitro potency is not related to the observed enzyme conformation. These findings will prove fundamental to enhance the potency of this series via rational structure-based drug-design approaches. |
| first_indexed | 2024-03-09T16:32:01Z |
| format | Article |
| id | doaj.art-145c2385716e4b2ea8af25a8fb2e5bd8 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T16:32:01Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-145c2385716e4b2ea8af25a8fb2e5bd82023-11-24T15:00:15ZengMDPI AGPharmaceuticals1424-82472023-11-011611155910.3390/ph16111559Structural Study of a New MbtI-Inhibitor Complex: Towards an Optimized Model for Structure-Based Drug DiscoveryMatteo Mori0Stefania Villa1Laurent R. Chiarelli2Fiorella Meneghetti3Marco Bellinzoni4Department of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyDepartment of Biology and Biotechnology “Lazzaro Spallanzani”, University of Pavia, Via A. Ferrata 9, 27100 Pavia, ItalyDepartment of Pharmaceutical Sciences, University of Milan, Via L. Mangiagalli 25, 20133 Milano, ItalyInstitut Pasteur, Université Paris Cité, CNRS UMR3528, Unité de Microbiologie Structurale, F-75015 Paris, FranceMbtI from <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) is a Mg<sup>2+</sup>-dependent salicylate synthase, belonging to the chorismate-utilizing enzyme (CUE) family. As a fundamental player in iron acquisition, MbtI promotes the survival and pathogenicity of <i>Mtb</i> in the infected host. Hence, it has emerged in the last decade as an innovative, potential target for the anti-virulence therapy of tuberculosis. In this context, 5-phenylfuran-2-carboxylic acids have been identified as potent MbtI inhibitors. The first co-crystal structure of MbtI in complex with a member of this class was described in 2020, showing the enzyme adopting an open configuration. Due to the high mobility of the loop adjacent to the binding pocket, large portions of the amino acid chain were not defined in the electron density map, hindering computational efforts aimed at structure-driven ligand optimization. Herein, we report a new, high-resolution co-crystal structure of MbtI with a furan-based derivative, in which the closed configuration of the enzyme allowed tracing the entirety of the active site pocket in the presence of the bound inhibitor. Moreover, we describe a new crystal structure of MbtI in open conformation and in complex with the known inhibitor methyl-AMT, suggesting that in vitro potency is not related to the observed enzyme conformation. These findings will prove fundamental to enhance the potency of this series via rational structure-based drug-design approaches.https://www.mdpi.com/1424-8247/16/11/1559<i>Mycobacterium tuberculosis</i>salicylate synthasesiderophoreironco-crystal structureanti-virulence therapy |
| spellingShingle | Matteo Mori Stefania Villa Laurent R. Chiarelli Fiorella Meneghetti Marco Bellinzoni Structural Study of a New MbtI-Inhibitor Complex: Towards an Optimized Model for Structure-Based Drug Discovery Pharmaceuticals <i>Mycobacterium tuberculosis</i> salicylate synthase siderophore iron co-crystal structure anti-virulence therapy |
| title | Structural Study of a New MbtI-Inhibitor Complex: Towards an Optimized Model for Structure-Based Drug Discovery |
| title_full | Structural Study of a New MbtI-Inhibitor Complex: Towards an Optimized Model for Structure-Based Drug Discovery |
| title_fullStr | Structural Study of a New MbtI-Inhibitor Complex: Towards an Optimized Model for Structure-Based Drug Discovery |
| title_full_unstemmed | Structural Study of a New MbtI-Inhibitor Complex: Towards an Optimized Model for Structure-Based Drug Discovery |
| title_short | Structural Study of a New MbtI-Inhibitor Complex: Towards an Optimized Model for Structure-Based Drug Discovery |
| title_sort | structural study of a new mbti inhibitor complex towards an optimized model for structure based drug discovery |
| topic | <i>Mycobacterium tuberculosis</i> salicylate synthase siderophore iron co-crystal structure anti-virulence therapy |
| url | https://www.mdpi.com/1424-8247/16/11/1559 |
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