4PY2

Crystal structure of methionyl-tRNA synthetase MetRS from Brucella melitensis in complex with inhibitor 1-{3-[(3,5-DICHLOROBENZYL)AMINO]PROPYL}-3-THIOPHEN-3-YLUREA

4PY2 の概要

• エントリーDOI: 10.2210/pdb4py2/pdb
• 関連するPDBエントリー: 4DLP 4LNE 4PPW
• 分子名称: Methionine--tRNA ligase, 1-{3-[(3,5-dichlorobenzyl)amino]propyl}-3-thiophen-3-ylurea, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: structural genomics, niaid, national institute of allergy and infectious diseases, seattle structural genomics center for infectious disease, ssgcid, ligase, methionyl-trna synthetase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Brucella melitensis
• 細胞内の位置: Cytoplasm : Q2YQ76
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 182522.63

構造登録者

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (登録日: 2014-03-25, 公開日: 2015-04-15, 最終更新日: 2025-10-22)

主引用文献

Ojo, K.K.,Ranade, R.M.,Zhang, Z.,Dranow, D.M.,Myers, J.B.,Choi, R.,Nakazawa Hewitt, S.,Edwards, T.E.,Davies, D.R.,Lorimer, D.,Boyle, S.M.,Barrett, L.K.,Buckner, F.S.,Fan, E.,Van Voorhis, W.C.
Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis.
Plos One, 11:e0160350-e0160350, 2016

PubMed Abstract: We investigated Brucella melitensis methionyl-tRNA-synthetase (BmMetRS) with molecular, structural and phenotypic methods to learn if BmMetRS is a promising target for brucellosis drug development. Recombinant BmMetRS was expressed, purified from wild type Brucella melitensis biovar Abortus 2308 strain ATCC/CRP #DD-156 and screened by a thermal melt assay against a focused library of one hundred previously classified methionyl-tRNA-synthetase inhibitors of the blood stage form of Trypanosoma brucei. Three compounds showed appreciable shift of denaturation temperature and were selected for further studies on inhibition of the recombinant enzyme activity and cell viability against wild type B. melitensis strain 16M. BmMetRS protein complexed with these three inhibitors resolved into three-dimensional crystal structures and was analyzed. All three selected methionyl-tRNA-synthetase compounds inhibit recombinant BmMetRS enzymatic functions in an aminoacylation assay at varying concentrations. Furthermore, growth inhibition of B. melitensis strain 16M by the compounds was shown. Inhibitor-BmMetRS crystal structure models were used to illustrate the molecular basis of the enzyme inhibition. Our current data suggests that BmMetRS is a promising target for brucellosis drug development. However, further studies are needed to optimize lead compound potency, efficacy and safety as well as determine the pharmacokinetics, optimal dosage, and duration for effective treatment.

PubMed: 27500735
DOI: 10.1371/journal.pone.0160350

実験手法

X-RAY DIFFRACTION (2.15 Å)