6VV2
Crystal structure of Eis from Mycobacterium tuberculosis in complex with inhibitor SGT1348
Summary for 6VV2
| Entry DOI | 10.2210/pdb6vv2/pdb |
| Descriptor | N-acetyltransferase Eis, 2-{[3-(piperidin-1-yl)propyl]sulfanyl}-6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-amine, DI(HYDROXYETHYL)ETHER, ... (9 entities in total) |
| Functional Keywords | acetyltransferase, resistance, aminoglycoside, competitive, 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 | 46806.55 |
| Authors | Punetha, A.,Hou, C.,Ngo, H.X.,Garneau-Tsodikova, S.,Tsodikov, O.V. (deposition date: 2020-02-16, release date: 2020-06-03, Last modification date: 2023-10-11) |
| Primary citation | Punetha, A.,Ngo, H.X.,Holbrook, S.Y.L.,Green, K.D.,Willby, M.J.,Bonnett, S.A.,Krieger, K.,Dennis, E.K.,Posey, J.E.,Parish, T.,Tsodikov, O.V.,Garneau-Tsodikova, S. Structure-Guided Optimization of Inhibitors of Acetyltransferase Eis fromMycobacterium tuberculosis. Acs Chem.Biol., 15:1581-1594, 2020 Cited by PubMed Abstract: The enhanced intracellular survival (Eis) protein of () is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of , we designed and optimized structurally unique thieno[2,3-]pyrimidine Eis inhibitors toward effective kanamycin adjuvant combination therapy. We obtained 12 crystal structures of enzyme-inhibitor complexes, which guided our rational structure-based design of 72 thieno[2,3-]pyrimidine analogues divided into three families. We evaluated the potency of these inhibitors as well as their ability to restore the activity of kanamycin in a resistant strain of , in which Eis was upregulated. Furthermore, we evaluated the metabolic stability of 11 compounds . This study showcases how structural information can guide Eis inhibitor design. PubMed: 32421305DOI: 10.1021/acschembio.0c00184 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.95 Å) |
Structure validation
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