Database accession: MF7000724
Name: TrmD, a tRNA-(N1G37) methyltransferase (Mycobacterium abscessus)
PDB ID: 6qqw
Experimental method: X-ray (1.80 Å)
Assembly: Homodimer
Source organism: Mycobacteroides abscessus
Primary publication of the structure:
Whitehouse AJ, Thomas SE, Brown KP, Fanourakis A, Chan DS, Libardo MDJ, Mendes V, Boshoff HIM, Floto RA, Abell C, Blundell TL, Coyne AG
Development of Inhibitors against tRNA (mG37) Methyltransferase (TrmD) Using Fragment-Based Approaches.
(2019) J. Med. Chem. 62: 7210-7232
PMID: 31282680
Abstract:
Mycobacterium abscessus (Mab) 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. Mab 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 Mab 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 Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab, supporting the use of TrmD as a target for the development of antimycobacterial compounds.
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: 1-232)
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)
Download this entry's JSON file (.json)
