8QC4

M. tuberculosis salicylate synthase MbtI in complex with 5-(3-carboxyphenyl)furan-2-carboxylic acid

This is a non-PDB format compatible entry.

Summary for 8QC4

• Entry DOI: 10.2210/pdb8qc4/pdb
• Descriptor: Salicylate synthase, 5-(3-carboxyphenyl)furan-2-carboxylic acid, SULFATE ION, ... (5 entities in total)
• Functional Keywords: salicylate, isochorismate, chorismate, mycobactins, lyase
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 2
• Total formula weight: 98839.49

Authors

Mori, M.,Villa, S.,Meneghetti, F.,Bellinzoni, M. (deposition date: 2023-08-25, release date: 2023-11-15, Last modification date: 2023-12-06)

Primary citation

Mori, M.,Villa, S.,Chiarelli, L.R.,Meneghetti, F.,Bellinzoni, M.
Structural Study of a New MbtI-Inhibitor Complex: Towards an Optimized Model for Structure-Based Drug Discovery.
Pharmaceuticals, 16:-, 2023

PubMed Abstract: MbtI from () is a Mg-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 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.

PubMed: 38004425
DOI: 10.3390/ph16111559

Experimental method

X-RAY DIFFRACTION (1.578 Å)