5EC4

Crystal structure of acetyltransferase Eis from Mycobacterium tuberculosis in complex with inhibitor 13g and CoA

5EC4 の概要

• エントリーDOI: 10.2210/pdb5ec4/pdb
• 関連するPDBエントリー: 5EBV
• 分子名称: Enhanced intracellular survival protein, COENZYME A, 5-(3-chlorophenyl)-4-methyl-~{N}-(3-morpholin-4-ylpropyl)-1,1-bis(oxidanylidene)-1,2-thiazol-3-amine, ... (4 entities in total)
• 機能のキーワード: transferase, aminoglycoside, resistance, tuberculosis, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47150.54

構造登録者

Gajadeera, C.S.,Hou, C.,Garneau-Tsodikova, S.,Tsodikov, O.V. (登録日: 2015-10-20, 公開日: 2016-03-30, 最終更新日: 2024-03-06)

主引用文献

Willby, M.J.,Green, K.D.,Gajadeera, C.S.,Hou, C.,Tsodikov, O.V.,Posey, J.E.,Garneau-Tsodikova, S.
Potent Inhibitors of Acetyltransferase Eis Overcome Kanamycin Resistance in Mycobacterium tuberculosis.
Acs Chem.Biol., 11:1639-1646, 2016

PubMed Abstract: A major cause of tuberculosis (TB) resistance to the aminoglycoside kanamycin (KAN) is the Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. Upregulation of this enzyme is responsible for inactivation of KAN through acetylation of its amino groups. A 123 000-compound high-throughput screen (HTS) yielded several small-molecule Eis inhibitors that share an isothiazole S,S-dioxide heterocyclic core. These were investigated for their structure-activity relationships. Crystal structures of Eis in complex with two potent inhibitors show that these molecules are bound in the conformationally adaptable aminoglycoside binding site of the enzyme, thereby obstructing binding of KAN for acetylation. Importantly, we demonstrate that several Eis inhibitors, when used in combination with KAN against resistant Mtb, efficiently overcome KAN resistance. This approach paves the way toward development of novel combination therapies against aminoglycoside-resistant TB.

PubMed: 27010218
DOI: 10.1021/acschembio.6b00110

実験手法

X-RAY DIFFRACTION (2.21 Å)