6P3V
Crystal structure of Eis from Mycobacterium tuberculosis in complex with inhibitor SGT416
Summary for 6P3V
| Entry DOI | 10.2210/pdb6p3v/pdb |
| Descriptor | N-acetyltransferase Eis, N,N-diethyl-2-[(8-fluoro-5-methyl-5H-[1,2,4]triazino[5,6-b]indol-3-yl)sulfanyl]ethan-1-amine, SULFATE ION, ... (5 entities in total) |
| Functional Keywords | acetyltransferase, aminoglycoside resistance, competitive inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Total number of polymer chains | 1 |
| Total formula weight | 46506.74 |
| Authors | Punetha, A.,Garneau-Tsodikova, S.,Tsodikov, O.V. (deposition date: 2019-05-24, release date: 2019-09-04, Last modification date: 2023-10-11) |
| Primary citation | Green, K.D.,Punetha, A.,Hou, C.,Garneau-Tsodikova, S.,Tsodikov, O.V. Probing the Robustness of Inhibitors of Tuberculosis Aminoglycoside Resistance Enzyme Eis by Mutagenesis. Acs Infect Dis., 5:1772-1778, 2019 Cited by PubMed Abstract: Each year, millions of people worldwide contract tuberculosis (TB), the deadliest infection. The spread of infections with drug-resistant strains of () that are refractory to treatment poses a major global challenge. A major cause of resistance to antitubercular drugs of last resort, aminoglycosides, is overexpression of the Eis (enhanced intracellular survival) enzyme of , which inactivates aminoglycosides by acetylating them. We showed previously that this inactivation of aminoglycosides could be overcome by our recently reported Eis inhibitors that are currently in development as potential aminoglycoside adjunctive therapeutics against drug-resistant TB. To interrogate the robustness of the Eis inhibitors, we investigated the enzymatic activity of Eis and its inhibition by Eis inhibitors from three different structural families for nine single-residue mutants of Eis, including those found in the clinic. Three engineered mutations of the substrate binding site, D26A, W36A, and F84A, abolished inhibitor binding while compromising Eis enzymatic activity 2- to 3-fold. All other Eis mutants, including clinically observed ones, were potently inhibited by at least one inhibitor. This study helps position us one step ahead of resistance to Eis inhibitors as they are being developed for TB therapy. PubMed: 31433614DOI: 10.1021/acsinfecdis.9b00228 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
Download full validation report
