6JOE

Crystal structure of TrmD from Pseudomonas aeruginosa in complex with active-site inhibitor

6JOE の概要

• エントリーDOI: 10.2210/pdb6joe/pdb
• 分子名称: tRNA (guanine-N(1)-)-methyltransferase, ~{N}-[[4-[(4-azanylpiperidin-1-yl)methyl]phenyl]methyl]-4-oxidanylidene-3~{H}-thieno[2,3-d]pyrimidine-5-carboxamide, PHOSPHATE ION, ... (5 entities in total)
• 機能のキーワード: trna methyltransferase, transferase
• 由来する生物種: Pseudomonas aeruginosa UCBPP-PA14
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 61563.23

構造登録者

Zhong, W.,Pasunooti, K.K.,Balamkundu, S.,Wong, Y.W.,Nah, Q.,Liu, C.F.,Lescar, J.,Dedon, P.C. (登録日: 2019-03-20, 公開日: 2019-09-04, 最終更新日: 2023-11-22)

主引用文献

Zhong, W.,Pasunooti, K.K.,Balamkundu, S.,Wong, Y.H.,Nah, Q.,Gadi, V.,Gnanakalai, S.,Chionh, Y.H.,McBee, M.E.,Gopal, P.,Lim, S.H.,Olivier, N.,Buurman, E.T.,Dick, T.,Liu, C.F.,Lescar, J.,Dedon, P.C.
Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-N1)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism.
J.Med.Chem., 62:7788-7805, 2019

PubMed 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-(NG37) methyltransferase, TrmD, which is an essential enzyme in many bacterial pathogens. On the basis of crystal structures of TrmDs from and , 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 TrmD and renders the enzyme inaccessible to the cofactor -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.

PubMed: 31442049
DOI: 10.1021/acs.jmedchem.9b00582

実験手法

X-RAY DIFFRACTION (2.21 Å)