36AP

Mycobacterium tuberculosis DNA Gyrase catalytic core in complex with DNA and indole-3-acetyl-L-aspartic acid

Summary for 36AP

• Entry DOI: 10.2210/pdb36ap/pdb
• EMDB information: 77331
• Descriptor: DNA gyrase subunit A, DNA gyrase subunit B, DNA (5'-D(P*AP*AP*TP*GP*CP*AP*CP*GP*TP*AP*T)-3'), ... (8 entities in total)
• Functional Keywords: mycobacterium tuberculosis, inha, inhibitory adduct, resistance, mutation, oxidoreductase
• Biological source: Mycobacterium tuberculosis; More
• Total number of polymer chains: 8
• Total formula weight: 181019.58

Authors

Rossini, N.O.,Dias, M.V.B.,Coureux, P.D. (deposition date: 2026-05-28, release date: 2026-10-28)

Primary citation

Shiroma, S.T.,Rossini, N.O.,Armenia, J.F.,Silva, C.S.,Souza, P.C.T.,Coureux, P.D.,Osheroff, N.,Dias, M.V.B.
Fragment-based drug discovery strategy reveals an unprecedented allosteric binding site in Mycobacterium tuberculosis DNA gyrase.
Eur.J.Med.Chem., 320:119380-119380, 2026

PubMed Abstract: Tuberculosis remains a serious public health threat and the leading infectious cause of death worldwide. Tuberculosis treatment requires at least four antimicrobial drugs and is associated with adverse effects and prolonged therapy, compromising adherence and increasing the risk of drug resistance. Therefore, developing new antitubercular therapies remains essential. Mycobacterium tuberculosis, the primary etiological agent of tuberculosis, lacks topoisomerase IV, making DNA gyrase its sole type II topoisomerase and an attractive drug target. Although fluoroquinolones such as moxifloxacin are used to treat tuberculosis, resistance has limited their effectiveness. Here, we applied a fragment-based drug discovery approach to identify and validate low-affinity compounds targeting M. tuberculosis DNA gyrase as starting points for inhibitor development. Using complementary biophysical and biochemical techniques, we identified five compounds that bind DNA gyrase and inhibit DNA supercoiling and DNA cleavage activities. These compounds interfere with early steps of the gyrase catalytic cycle, likely by blocking conformational changes required for DNA cleavage. The cryo-electron microscopy structure of DNA gyrase in complex with the most potent compound revealed binding near the GyrA-GyrB interface and extensive conformational changes in the GyrB TOPRIM domain. These findings provide a foundation for developing antitubercular agents with a novel mechanism of action.

PubMed: 42822253
DOI: 10.1016/j.ejmech.2026.119380

Experimental method

ELECTRON MICROSCOPY (2.64 Å)