6P3T

Crystal structure of Eis from Mycobacterium tuberculosis in complex with inhibitor SGT449

6P3T の概要

• エントリーDOI: 10.2210/pdb6p3t/pdb
• 分子名称: N-acetyltransferase Eis, N-methyl-N-(naphthalen-2-yl)-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide, GLYCEROL, ... (8 entities in total)
• 機能のキーワード: acetyltransferase, aminoglycoside resistance, competitive inhibitor, 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: 47303.55

構造登録者

Punetha, A.,Garneau-Tsodikova, S.,Tsodikov, O.V. (登録日: 2019-05-24, 公開日: 2019-09-04, 最終更新日: 2023-10-11)

主引用文献

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

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: 31433614
DOI: 10.1021/acsinfecdis.9b00228

実験手法

X-RAY DIFFRACTION (2.5 Å)