MF7000724 TrmD, a tRNA-(N1G37) methyltransferase (Mycobacterium abscessus) 6qqw X-ray 1.80 Homodimer Mycobacteroides abscessus 31282680 Whitehouse AJ, Thomas SE, Brown KP, Fanourakis A, Chan DS, Libardo MDJ, Mendes V, Boshoff HIM, Floto RA, Abell C, Blundell TL, Coyne AG J. Med. Chem. 2019 15 62 7210-7232 <i>Mycobacterium abscessus</i> (<i>Mab</i>) 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. <i>Mab</i> 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 (m₁G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in <i>Mab</i> 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 <i>Mab</i> TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including <i>Mycobacterium tuberculosis</i> and <i>Mycobacterium leprae</i> in addition to <i>Mab</i>, supporting the use of TrmD as a target for the development of antimycobacterial compounds. GO:0052906 tRNA (guanine(37)-N1)-methyltransferase activity GO:0005829 cytosol GO:0002939 tRNA N1-guanine methylation 2 1 Homooligomeric enzymes Homodimeric enzymes All chains according to the most probable oligomerization state stored in PDBe were considered. A tRNA (guanine-N(1)-)-methyltransferase Mycobacteroides abscessus B1MDI3 1 227 93% MKIDVVTIFPEYLQPVRQSLPGKAIDAGLVDVAVHDLRRWTHDVHKSVDDSPYGGGPGMVMKPTVWGDALDEICTSETLLVVPTPAGYPFTQETAWQWSTEDHLVIACGRYEGIDQRVADDAATRMRVREVSIGDYVLNGGEAAALVIIEAVLRLVPGVLGNALSAQEDSHSEGMASLLEGPSYTRPPSWRGMDVPPVLLSGDHAKIAAWRAEQSRQRTIERRPDLLGFDSPTGEHGGDGLS 242 secondary structure helix 11 14 secondary structure helix 15 22 secondary structure helix 23 29 secondary structure helix 40 43 secondary structure helix 64 76 secondary structure helix 93 101 secondary structure helix 118 125 secondary structure helix 143 156 secondary structure helix 198 203 secondary structure helix 205 225 secondary structure helix 226 229 secondary structure strand 3 9 secondary structure strand 32 38 secondary structure strand 51 52 secondary structure strand 62 63 secondary structure strand 81 85 secondary structure strand 90 91 secondary structure strand 105 109 secondary structure strand 129 134 secondary structure strand 191 192 secondary structure strand 195 196 pfam PF01746 tRNA (Guanine-1)-methyltransferase 22 224 B tRNA (guanine-N(1)-)-methyltransferase Mycobacteroides abscessus B1MDI3 1 232 95% MKIDVVTIFPEYLQPVRQSLPGKAIDAGLVDVAVHDLRRWTHDVHKSVDDSPYGGGPGMVMKPTVWGDALDEICTSETLLVVPTPAGYPFTQETAWQWSTEDHLVIACGRYEGIDQRVADDAATRMRVREVSIGDYVLNGGEAAALVIIEAVLRLVPGVLGNALSAQEDSHSEGMASLLEGPSYTRPPSWRGMDVPPVLLSGDHAKIAAWRAEQSRQRTIERRPDLLGFDSPTGEHGGDGLS 242 secondary structure helix 11 16 secondary structure helix 40 43 secondary structure helix 64 76 secondary structure helix 93 101 secondary structure helix 118 126 secondary structure helix 143 156 secondary structure helix 199 204 secondary structure helix 205 225 secondary structure helix 226 230 secondary structure strand 3 9 secondary structure strand 32 38 secondary structure strand 51 52 secondary structure strand 62 63 secondary structure strand 81 85 secondary structure strand 90 91 secondary structure strand 105 109 secondary structure strand 129 134 secondary structure strand 191 192 secondary structure strand 195 196 pfam PF01746 tRNA (Guanine-1)-methyltransferase 22 224 Indirect evidence The full structure participates in mutual synergistic folding. tRNA (Guanine-1)-methyltransferase Multisubdomain structure, where both subdomains participate in dimerization. The C-terminal domain is TRP repressor-like. The structure suggests that the dimer is the functional form of the protein since it has an extensive and tight hydrophobic interface and a large buried surface area. DLS data of the protein solution suggest that the A. aeolicus tRNA (m1G37) methyltransferase is oligomeric (dimer or trimer) in solution (PMID:12773376). The active site is also located at the subunit interface (PMID:14517984). A N/A B N/A MF7000723 MF7000724 MF7000725 MF7000726 MF7000727 MF7000728 MF7000729 MF7000730 MF7000731 MF7000732 MF7000733 MF7000734 MF7000735 MF7000736 MF7000737 MF7000738