8F4W

Crystal structure of acetyltransferase Eis from M. tuberculosis in complex with venlafaxine

8F4W の概要

• エントリーDOI: 10.2210/pdb8f4w/pdb
• 分子名称: N-acetyltransferase Eis, 1-[(1R)-2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol, DIMETHYL SULFOXIDE, ... (6 entities in total)
• 機能のキーワード: drug resistance, inhibitor, acetylation, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Mycobacterium tuberculosis H37Rv
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 47211.55

構造登録者

Pang, A.H.,Punetha, A.,Garneau-Tsodikova, S.,Tsodikov, O.V. (登録日: 2022-11-11, 公開日: 2023-02-01, 最終更新日: 2023-10-25)

主引用文献

Pang, A.H.,Green, K.D.,Punetha, A.,Thamban Chandrika, N.,Howard, K.C.,Garneau-Tsodikova, S.,Tsodikov, O.V.
Discovery and Mechanistic Analysis of Structurally Diverse Inhibitors of Acetyltransferase Eis among FDA-Approved Drugs.
Biochemistry, 62:710-721, 2023

PubMed Abstract: Over one and a half million people die of tuberculosis (TB) each year. Multidrug-resistant TB infections are especially dangerous, and new drugs are needed to combat them. The high cost and complexity of drug development make repositioning of drugs that are already in clinical use for other indications a potentially time- and money-saving avenue. In this study, we identified among existing drugs five compounds: azelastine, venlafaxine, chloroquine, mefloquine, and proguanil as inhibitors of acetyltransferase Eis from , a causative agent of TB. Eis upregulation is a cause of clinically relevant resistance of TB to kanamycin, which is inactivated by Eis-catalyzed acetylation. Crystal structures of these drugs as well as chlorhexidine in complexes with Eis showed that these inhibitors were bound in the aminoglycoside binding cavity, consistent with their established modes of inhibition with respect to kanamycin. Among three additionally synthesized compounds, a proguanil analogue, designed based on the crystal structure of the Eis-proguanil complex, was 3-fold more potent than proguanil. The crystal structures of these compounds in complexes with Eis explained their inhibitory potencies. These initial efforts in rational drug repositioning can serve as a starting point in further development of Eis inhibitors.

PubMed: 36657084
DOI: 10.1021/acs.biochem.2c00658

実験手法

X-RAY DIFFRACTION (2.1 Å)