7KMY
Structure of Mtb Lpd bound to 010705
Summary for 7KMY
| Entry DOI | 10.2210/pdb7kmy/pdb |
| Related | 4M52 |
| Descriptor | Dihydrolipoyl dehydrogenase, FLAVIN-ADENINE DINUCLEOTIDE, N~2~-methyl-N~2~-[(5-methyl-1H-indazol-7-yl)sulfonyl]-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)glycinamide, ... (5 entities in total) |
| Functional Keywords | flavoprotein, glycolysis, redox-active center, inhibitor, oxidoreductase/oxidoreductase inhibitor, oxidoreductase-oxidoreductase inhibitor complex |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Total number of polymer chains | 8 |
| Total formula weight | 408303.59 |
| Authors | Lima, C.D. (deposition date: 2020-11-03, release date: 2021-01-27, Last modification date: 2023-10-18) |
| Primary citation | Ginn, J.,Jiang, X.,Sun, S.,Michino, M.,Huggins, D.J.,Mbambo, Z.,Jansen, R.,Rhee, K.Y.,Arango, N.,Lima, C.D.,Liverton, N.,Imaeda, T.,Okamoto, R.,Kuroita, T.,Aso, K.,Stamford, A.,Foley, M.,Meinke, P.T.,Nathan, C.,Bryk, R. Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions. Acs Infect Dis., 7:435-444, 2021 Cited by PubMed Abstract: Tuberculosis remains a leading cause of death from a single bacterial infection worldwide. Efforts to develop new treatment options call for expansion into an unexplored target space to expand the drug pipeline and bypass resistance to current antibiotics. Lipoamide dehydrogenase is a metabolic and antioxidant enzyme critical for mycobacterial growth and survival in mice. Sulfonamide analogs were previously identified as potent and selective inhibitors of mycobacterial lipoamide dehydrogenase but lacked activity against whole mycobacteria. Here we present the development of analogs with improved permeability, potency, and selectivity, which inhibit the growth of in axenic culture on carbohydrates and within mouse primary macrophages. They increase intrabacterial pyruvate levels, supporting their on-target activity within mycobacteria. Distinct modalities of binding between the mycobacterial and human enzymes contribute to improved potency and hence selectivity through induced-fit tight binding interactions within the mycobacterial but not human enzyme, as indicated by kinetic analysis and crystallography. PubMed: 33527832DOI: 10.1021/acsinfecdis.0c00788 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.21 Å) |
Structure validation
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