4DRE
Mycobacterium tuberculosis InhA in complex with NADH
Summary for 4DRE
| Entry DOI | 10.2210/pdb4dre/pdb |
| Related | 4DQU |
| Descriptor | Enoyl-[acyl-carrier-protein] reductase [NADH], 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE (3 entities in total) |
| Functional Keywords | enoyl-acp reductase, oxidoreductase |
| Biological source | Mycobacterium tuberculosis |
| Total number of polymer chains | 1 |
| Total formula weight | 29220.22 |
| Authors | Pojer, F.,Hartkoorn, R.C.,Boy, S.,Cole, S.T. (deposition date: 2012-02-17, release date: 2012-10-03, Last modification date: 2024-02-28) |
| Primary citation | Hartkoorn, R.C.,Sala, C.,Neres, J.,Pojer, F.,Magnet, S.,Mukherjee, R.,Uplekar, S.,Boy-Rottger, S.,Altmann, K.H.,Cole, S.T. Towards a new tuberculosis drug: pyridomycin - nature's isoniazid. EMBO Mol Med, 4:1032-1042, 2012 Cited by PubMed Abstract: Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA-inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti-tuberculosis agents. Here, we describe pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin-resistant mutants of Mycobacterium tuberculosis, whole-genome sequencing and genetic validation, we identified the NADH-dependent enoyl- (Acyl-Carrier-Protein) reductase InhA as the principal target and demonstrate that pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH-binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid-resistant clinical isolates remain fully susceptible to pyridomycin, thus opening new avenues for drug development. →See accompanying article http://dx.doi.org/10.1002/emmm.201201811. PubMed: 22987724DOI: 10.1002/emmm.201201689 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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