6VUS

Crystal structure of Eis from Mycobacterium tuberculosis in complex with inhibitor SGT379

6VUS の概要

• エントリーDOI: 10.2210/pdb6vus/pdb
• 分子名称: N-acetyltransferase Eis, 2-[(4-amino-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-2-yl)sulfanyl]-N-[2-(diethylamino)ethyl]acetamide, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: acetyltransferase, resistance, aminoglycoside, competitive, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46970.44

構造登録者

Punetha, A.,Hou, C.,Ngo, H.X.,Garneau-Tsodikova, S.,Tsodikov, O.V. (登録日: 2020-02-16, 公開日: 2020-06-03, 最終更新日: 2023-10-11)

主引用文献

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

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: 32421305
DOI: 10.1021/acschembio.0c00184

実験手法

X-RAY DIFFRACTION (2.28 Å)