PDBsum entry 6joe

Transferase

PDB id: 6joe

Contents

Protein chains

242 a.a.

Ligands

BWR

PO4

SAM

Waters ×191

References listed in PDB file

Key reference

• Title: Thienopyrimidinone derivatives that inhibit bacterial tRNA (guanine37-n¹)-Methyltransferase (trmd) by restructuring the active site with a tyrosine-Flipping mechanism.
• Authors: W.Zhong, K.K.Pasunooti, S.Balamkundu, Y.H.Wong, Q.Nah, V.Gadi, S.Gnanakalai, Y.H.Chionh, M.E.Mcbee, P.Gopal, S.H.Lim, N.Olivier, E.T.Buurman, T.Dick, C.F.Liu, J.Lescar, P.C.Dedon.
• Ref.: J Med Chem, 2019, 62, 7788-7805. [DOI no: 10.1021/acs.jmedchem.9b00582]
• PubMed id: 31442049

Abstract

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-(N¹G37) 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.