{"entry": {"accession": "MF7000735", "general": {"name": "TrmD, a tRNA-(N1G37) methyltransferasewith Fragment 16 (2-Amino-3-nitropyridine) (Mycobacteroides abscessus)", "pdb_id": "6qom", "exp_method": "X-ray", "resolution": "1.90", "assembly": "Homodimer", "source_organism": "Mycobacteroides abscessus", "publication": {"pmid": "32602532", "authors": "Thomas SE, Whitehouse AJ, Brown K, Burbaud S, Belardinelli JM, Sangen J, Lahiri R, Libardo MDJ, Gupta P, Malhotra S, Boshoff HIM, Jackson M, Abell C, Coyne AG, Blundell TL, Floto RA, Mendes V", "title": "Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification.", "journal": "Nucleic Acids Res.", "year": "2020", "issue": "14", "volume": "48", "pages": "8099-8112", "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."}}, "function": {"molecular_function": {"go": {"accession": "GO:0052906", "name": "tRNA (guanine(37)-N1)-methyltransferase activity"}}, "cellular_component": {"go": {"accession": "GO:0005829", "name": "cytosol"}}, "biological_process": {"go": {"accession": "GO:0002939", "name": "tRNA N1-guanine methylation"}}}, "macromolecules": {"general": {"nr_of_chains": "2", "nr_of_unique_protein_segments": "1", "class": "Homooligomeric enzymes", "subclass": "Homodimeric enzymes", "note": "All chains according to the most probable oligomerization state stored in PDBe were considered."}, "chain": [{"id": "A", "name": "tRNA (guanine-N(1)-)-methyltransferase", "source_organism": "Mycobacteroides abscessus", "uniprot": {"id": "B1MDI3", "start": "1", "end": "228", "coverage": "94%", "sequence": "MKIDVVTIFPEYLQPVRQSLPGKAIDAGLVDVAVHDLRRWTHDVHKSVDDSPYGGGPGMVMKPTVWGDALDEICTSETLLVVPTPAGYPFTQETAWQWSTEDHLVIACGRYEGIDQRVADDAATRMRVREVSIGDYVLNGGEAAALVIIEAVLRLVPGVLGNALSAQEDSHSEGMASLLEGPSYTRPPSWRGMDVPPVLLSGDHAKIAAWRAEQSRQRTIERRPDLLGFDSPTGEHGGDGLS", "length": "242"}, "regions": {"region": [{"region_type": "secondary structure", "region_name": "helix", "region_start": "40", "region_end": "43"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "64", "region_end": "76"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "93", "region_end": "101"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "117", "region_end": "125"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "143", "region_end": "156"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "198", "region_end": "203"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "205", "region_end": "225"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "226", "region_end": "230"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "3", "region_end": "9"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "32", "region_end": "38"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "51", "region_end": "52"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "62", "region_end": "63"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "81", "region_end": "85"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "90", "region_end": "91"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "105", "region_end": "109"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "129", "region_end": "134"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "191", "region_end": "192"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "195", "region_end": "196"}, {"region_type": "pfam", "region_id": "PF01746", "region_name": "tRNA (Guanine-1)-methyltransferase", "region_start": "22", "region_end": "224"}]}}, {"id": "B", "name": "tRNA (guanine-N(1)-)-methyltransferase", "source_organism": "Mycobacteroides abscessus", "uniprot": {"id": "B1MDI3", "start": "1", "end": "232", "coverage": "95%", "sequence": "MKIDVVTIFPEYLQPVRQSLPGKAIDAGLVDVAVHDLRRWTHDVHKSVDDSPYGGGPGMVMKPTVWGDALDEICTSETLLVVPTPAGYPFTQETAWQWSTEDHLVIACGRYEGIDQRVADDAATRMRVREVSIGDYVLNGGEAAALVIIEAVLRLVPGVLGNALSAQEDSHSEGMASLLEGPSYTRPPSWRGMDVPPVLLSGDHAKIAAWRAEQSRQRTIERRPDLLGFDSPTGEHGGDGLS", "length": "242"}, "regions": {"region": [{"region_type": "secondary structure", "region_name": "helix", "region_start": "11", "region_end": "16"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "40", "region_end": "43"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "64", "region_end": "76"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "93", "region_end": "101"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "117", "region_end": "126"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "143", "region_end": "156"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "198", "region_end": "203"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "205", "region_end": "225"}, {"region_type": "secondary structure", "region_name": "helix", "region_start": "226", "region_end": "230"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "3", "region_end": "9"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "32", "region_end": "38"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "51", "region_end": "52"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "62", "region_end": "63"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "81", "region_end": "85"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "90", "region_end": "91"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "105", "region_end": "109"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "129", "region_end": "134"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "191", "region_end": "192"}, {"region_type": "secondary structure", "region_name": "strand", "region_start": "195", "region_end": "196"}, {"region_type": "pfam", "region_id": "PF01746", "region_name": "tRNA (Guanine-1)-methyltransferase", "region_start": "22", "region_end": "224"}]}}]}, "evidence": {"evidence_level": "Indirect evidence", "evidence_coverage": "The full structure participates in mutual synergistic folding.", "sequence_domain": "tRNA (Guanine-1)-methyltransferase", "complex_evidence": "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).", "chain_evidence": [{"chain_id": "A", "support": "N/A"}, {"chain_id": "B", "support": "N/A"}]}, "related_structures": {"id": ["MF7000723", "MF7000724", "MF7000725", "MF7000726", "MF7000727", "MF7000728", "MF7000729", "MF7000730", "MF7000731", "MF7000732", "MF7000733", "MF7000734", "MF7000735", "MF7000736", "MF7000737", "MF7000738"]}}}