6QOF
Crystal structure of TrmD, a tRNA-(N1G37) methyltransferase, from Mycobacterium abscessus in complex with Fragment 9 (Adenine)
Summary for 6QOF
| Entry DOI | 10.2210/pdb6qof/pdb |
| Related | 6NVR |
| Descriptor | tRNA (guanine-N(1)-)-methyltransferase, ADENINE, 1,2-ETHANEDIOL, ... (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 | 53263.73 |
| Authors | Thomas, S.E.,Whitehouse, A.J.,Coyne, A.G.,Abell, C.,Mendes, V.,Blundell, T.L. (deposition date: 2019-02-12, release date: 2020-02-26, Last modification date: 2024-05-15) |
| 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 Cited by 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: 32602532DOI: 10.1093/nar/gkaa539 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.76 Å) |
Structure validation
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