6QR4

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

Summary for 6QR4

• Entry DOI: 10.2210/pdb6qr4/pdb
• Related: 6NVR
• Descriptor: 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)
• Functional Keywords: trmd, trna methyltransferase, spout methyltransferase, transferase
• Biological source: Mycobacterium abscessus
• Total number of polymer chains: 2
• Total formula weight: 53538.18

Authors

Thomas, S.E.,Whitehouse, A.J.,Coyne, A.G.,Abell, C.,Mendes, V.,Blundell, T.L. (deposition date: 2019-02-19, release date: 2019-09-18, Last modification date: 2024-01-24)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.52 Å)