Database accession: MF7000733
Name: TrmD, a tRNA-(N1G37) methyltransferase with Fragment 12 (2-Aminobenzothiazole) (Mycobacteroides abscessus)
PDB ID: 6qoi
Experimental method: X-ray (1.86 Å)
Assembly: Homodimer
Source organism: Mycobacteroides abscessus
Primary publication of the structure:
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
Fragment-based discovery of a new class of inhibitors targeting mycobacterial tRNA modification.
(2020) Nucleic Acids Res. 48: 8099-8112
PMID: 32602532
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.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
tRNA (guanine(37)-N1)-methyltransferase activity tRNA (guanine(37)-N1)-methyltransferase activity
Biological process:
tRNA N1-guanine methylation tRNA N1-guanine methylation
Cellular component:
cytosol cytosol
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: A, B
Notes: All chains according to the most probable oligomerization state stored in PDBe were considered.
Number of unique protein segments: 1
Name: tRNA (guanine-N(1)-)-methyltransferase
Source organism: Mycobacteroides abscessus
Length: 242 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMKIDVVTIFPEYLQPVRQSLPGKAIDAGLVDVAVHDLRRWTHDVHKSVDDSPYGGGPGMVMKPTVWGDALDEICTSETLLVVPTPAGYPFTQETAWQWSTEDHLVIACGRYEGIDQRVADDAATRMRVREVSIGDYVLNGGEAAALVIIEAVLRLVPGVLGNALSAQEDSHSEGMASLLEGPSYTRPPSWRGMDVPPVLLSGDHAKIAAWRAEQSRQRTIERRPDLLGFDSPTGEHGGDGLS
UniProtKB AC: B1MDI3 (positions: 1-227)
Coverage: 93%
Name: tRNA (guanine-N(1)-)-methyltransferase
Source organism: Mycobacteroides abscessus
Length: 242 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMKIDVVTIFPEYLQPVRQSLPGKAIDAGLVDVAVHDLRRWTHDVHKSVDDSPYGGGPGMVMKPTVWGDALDEICTSETLLVVPTPAGYPFTQETAWQWSTEDHLVIACGRYEGIDQRVADDAATRMRVREVSIGDYVLNGGEAAALVIIEAVLRLVPGVLGNALSAQEDSHSEGMASLLEGPSYTRPPSWRGMDVPPVLLSGDHAKIAAWRAEQSRQRTIERRPDLLGFDSPTGEHGGDGLS
UniProtKB AC: B1MDI3 (positions: 1-231)
Coverage: 95%
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Representative domain in related structures: tRNA (Guanine-1)-methyltransferase
Evidence level: Indirect evidence
Evidence coverage: The full structure participates in mutual synergistic folding.
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 A:
N/A
Chain B:
N/A
Surface and contacts features:
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). Download the CIF file (.cif)
Download this entry's XML file (.xml)
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