4DQU

Mycobacterium tuberculosis InhA-D148G mutant in complex with NADH

Summary for 4DQU

• Entry DOI: 10.2210/pdb4dqu/pdb
• 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: 29162.18

Authors

Pojer, F.,Hartkoorn, R.C.,Boy, S.,Cole, S.T. (deposition date: 2012-02-16, 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

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: 22987724
DOI: 10.1002/emmm.201201689

Experimental method

X-RAY DIFFRACTION (2.45 Å)