5IV0
Crystal structure of Eis from Mycobacterium tuberculosis in complex with sulfonamide inhibitor 39 and coenzyme A
Summary for 5IV0
| Entry DOI | 10.2210/pdb5iv0/pdb |
| Descriptor | Enhanced intracellular survival protein, COENZYME A, N-(3-methoxyphenyl)-N-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide, ... (5 entities in total) |
| Functional Keywords | transferase, acetyltransferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh) |
| Total number of polymer chains | 1 |
| Total formula weight | 47896.10 |
| Authors | Gajadeera, C.S.,Hou, C.,Garneau-Tsodikova, S.,Tsodikov, O.V. (deposition date: 2016-03-18, release date: 2017-01-11, Last modification date: 2024-03-06) |
| Primary citation | Garzan, A.,Willby, M.J.,Green, K.D.,Gajadeera, C.S.,Hou, C.,Tsodikov, O.V.,Posey, J.E.,Garneau-Tsodikova, S. Sulfonamide-Based Inhibitors of Aminoglycoside Acetyltransferase Eis Abolish Resistance to Kanamycin in Mycobacterium tuberculosis. J. Med. Chem., 59:10619-10628, 2016 Cited by PubMed Abstract: A two-drug combination therapy where one drug targets an offending cell and the other targets a resistance mechanism to the first drug is a time-tested, yet underexploited approach to combat or prevent drug resistance. By high-throughput screening, we identified a sulfonamide scaffold that served as a pharmacophore to generate inhibitors of Mycobacterium tuberculosis acetyltransferase Eis, whose upregulation causes resistance to the aminoglycoside (AG) antibiotic kanamycin A (KAN) in Mycobacterium tuberculosis. Rational systematic derivatization of this scaffold to maximize Eis inhibition and abolish the Eis-mediated KAN resistance of M. tuberculosis yielded several highly potent agents. A crystal structure of Eis in complex with one of the most potent inhibitors revealed that the inhibitor bound Eis in the AG-binding pocket held by a conformationally malleable region of Eis (residues 28-37) bearing key hydrophobic residues. These Eis inhibitors are promising leads for preclinical development of innovative AG combination therapies against resistant TB. PubMed: 27933949DOI: 10.1021/acs.jmedchem.6b01161 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
Download full validation report
