4M52
Structure of Mtb Lpd bound to SL827
Summary for 4M52
| Entry DOI | 10.2210/pdb4m52/pdb |
| Related | 2A8X 3II4 |
| Descriptor | Dihydrolipoyl dehydrogenase, FLAVIN-ADENINE DINUCLEOTIDE, N~2~-[(2-amino-5-bromopyridin-3-yl)sulfonyl]-N-(4-methoxyphenyl)-N~2~-methylglycinamide, ... (4 entities in total) |
| Functional Keywords | oxidoreductase, flavoprotein, glycolysis, redox-active center |
| Biological source | Mycobacterium tuberculosis |
| Cellular location | Cytoplasm (Potential): P66004 |
| Total number of polymer chains | 4 |
| Total formula weight | 202607.50 |
| Authors | Lima, C.D. (deposition date: 2013-08-07, release date: 2013-11-27, Last modification date: 2024-11-20) |
| Primary citation | Bryk, R.,Arango, N.,Maksymiuk, C.,Balakrishnan, A.,Wu, Y.T.,Wong, C.H.,Masquelin, T.,Hipskind, P.,Lima, C.D.,Nathan, C. Lipoamide channel-binding sulfonamides selectively inhibit mycobacterial lipoamide dehydrogenase. Biochemistry, 52:9375-9384, 2013 Cited by PubMed Abstract: Tuberculosis remains a global health emergency that calls for treatment regimens directed at new targets. Here we explored lipoamide dehydrogenase (Lpd), a metabolic and detoxifying enzyme in Mycobacterium tuberculosis (Mtb) whose deletion drastically impairs Mtb's ability to establish infection in the mouse. Upon screening more than 1.6 million compounds, we identified N-methylpyridine 3-sulfonamides as potent and species-selective inhibitors of Mtb Lpd affording >1000-fold selectivity versus the human homologue. The sulfonamides demonstrated low nanomolar affinity and bound at the lipoamide channel in an Lpd-inhibitor cocrystal. Their selectivity could be attributed, at least partially, to hydrogen bonding of the sulfonamide amide oxygen with the species variant Arg93 in the lipoamide channel. Although potent and selective, the sulfonamides did not enter mycobacteria, as determined by their inability to accumulate in Mtb to effective levels or to produce changes in intracellular metabolites. This work demonstrates that high potency and selectivity can be achieved at the lipoamide-binding site of Mtb Lpd, a site different from the NAD⁺/NADH pocket targeted by previously reported species-selective triazaspirodimethoxybenzoyl inhibitors. PubMed: 24251446DOI: 10.1021/bi401077f PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
Download full validation report
