6QR4

Crystal structure of TrmD, a tRNA-(N1G37) methyltransferase, from Mycobacterium abscessus in complex with inhibitor

6QR4 の概要

• エントリーDOI: 10.2210/pdb6qr4/pdb
• 関連するPDBエントリー: 6NVR
• 分子名称: tRNA (guanine-N(1)-)-methyltransferase, 5-azanyl-3-[1-[[(2~{R})-1-methylpiperidin-2-yl]methyl]indol-6-yl]-1~{H}-pyrazole-4-carbonitrile (3 entities in total)
• 機能のキーワード: trmd, trna methyltransferase, spout methyltransferase, transferase
• 由来する生物種: Mycobacterium abscessus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 53538.18

構造登録者

Thomas, S.E.,Whitehouse, A.J.,Coyne, A.G.,Abell, C.,Mendes, V.,Blundell, T.L. (登録日: 2019-02-19, 公開日: 2019-09-18, 最終更新日: 2024-01-24)

主引用文献

Whitehouse, A.J.,Thomas, S.E.,Brown, K.P.,Fanourakis, A.,Chan, D.S.,Libardo, M.D.J.,Mendes, V.,Boshoff, H.I.M.,Floto, R.A.,Abell, C.,Blundell, T.L.,Coyne, A.G.
Development of Inhibitors against Mycobacterium abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches.
J.Med.Chem., 62:7210-7232, 2019

PubMed Abstract: () is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (mG37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work, a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including and in addition to , supporting the use of TrmD as a target for the development of antimycobacterial compounds.

PubMed: 31282680
DOI: 10.1021/acs.jmedchem.9b00809

実験手法

X-RAY DIFFRACTION (1.52 Å)