5zhk

Crystal structure of TrmD from Mycobacterium tuberculosis in complex with active-site inhibitor

spinqualitylabelsall models 5zhk, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5zhk is a 1 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: 9D6 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function TRMD_MYCTU Specifically methylates guanosine-37 in various tRNAs. Publication Abstract from PubMed Among the >120 modified ribonucleosides in the prokaryotic epitranscriptome, many tRNA modifications are critical to bacterial survival, which makes their synthetic enzymes ideal targets for antibiotic development. Here we performed a structure-based design of inhibitors of tRNA-(N(1)G37) methyltransferase, TrmD, which is an essential enzyme in many bacterial pathogens. On the basis of crystal structures of TrmDs from Pseudomonas aeruginosa and Mycobacterium tuberculosis, we synthesized a series of thienopyrimidinone derivatives with nanomolar potency against TrmD in vitro and discovered a novel active site conformational change triggered by inhibitor binding. This tyrosine-flipping mechanism is uniquely found in P. aeruginosa TrmD and renders the enzyme inaccessible to the cofactor S-adenosyl-l-methionine (SAM) and probably to the substrate tRNA. Biophysical and biochemical structure-activity relationship studies provided insights into the mechanisms underlying the potency of thienopyrimidinones as TrmD inhibitors, with several derivatives found to be active against Gram-positive and mycobacterial pathogens. These results lay a foundation for further development of TrmD inhibitors as antimicrobial agents. Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-N(1))-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism.,Zhong W, Pasunooti KK, Balamkundu S, Wong YH, Nah Q, Gadi V, Gnanakalai S, Chionh YH, McBee ME, Gopal P, Lim SH, Olivier N, Buurman ET, Dick T, Liu CF, Lescar J, Dedon PC J Med Chem. 2019 Sep 12;62(17):7788-7805. doi: 10.1021/acs.jmedchem.9b00582. Epub , 2019 Aug 29. PMID:31442049 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also TRNA methyltransferase 3D structures

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