6NW7

Crystal structure of TrmD, a tRNA-(N1G37) methyltransferase, from Mycobacterium abscessus in complex with S-Adenosyl-L-homocysteine

Summary for 6NW7

• Entry DOI: 10.2210/pdb6nw7/pdb
• Related: 6NVR
• Descriptor: tRNA (guanine-N(1)-)-methyltransferase, S-ADENOSYL-L-HOMOCYSTEINE, SULFATE ION, ... (4 entities in total)
• Functional Keywords: trmd, trna methyltransferase, spout methyltransferase, transferase
• Biological source: Mycobacterium abscessus
• Total number of polymer chains: 2
• Total formula weight: 53734.22

Authors

Thomas, S.E.,Whitehouse, A.J.,Coyne, A.G.,Abell, C.,Mendes, V.,Blundell, T.L. (deposition date: 2019-02-06, release date: 2020-02-19, Last modification date: 2024-01-24)

Primary citation

Thomas, S.E.,Whitehouse, A.J.,Brown, K.,Burbaud, S.,Belardinelli, J.M.,Sangen, J.,Lahiri, R.,Libardo, M.D.J.,Gupta, P.,Malhotra, S.,Boshoff, H.I.M.,Jackson, M.,Abell, C.,Coyne, A.G.,Blundell, T.L.,Floto, R.A.,Mendes, V.
Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification.
Nucleic Acids Res., 48:8099-8112, 2020

PubMed Abstract: Translational frameshift errors are often deleterious to the synthesis of functional proteins and could therefore be promoted therapeutically to kill bacteria. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and represents an attractive potential target for the development of new antibiotics. Here, we describe the application of a structure-guided fragment-based drug discovery approach to the design of a new class of inhibitors against TrmD in Mycobacterium abscessus. Fragment library screening, followed by structure-guided chemical elaboration of hits, led to the rapid development of drug-like molecules with potent in vitro TrmD inhibitory activity. Several of these compounds exhibit activity against planktonic M. abscessus and M. tuberculosis as well as against intracellular M. abscessus and M. leprae, indicating their potential as the basis for a novel class of broad-spectrum mycobacterial drugs.

PubMed: 32602532
DOI: 10.1093/nar/gkaa539

Experimental method

X-RAY DIFFRACTION (1.481 Å)