5K0S

Crystal structure of methionyl-tRNA synthetase MetRS from Brucella melitensis in complex with inhibitor Chem 1312

Replaces:  4LNE

Summary for 5K0S

• Entry DOI: 10.2210/pdb5k0s/pdb
• Related: 5K0T
• Descriptor: Methionine--tRNA ligase, 2-({3-[(3,5-dichlorobenzyl)amino]propyl}amino)quinolin-4(1H)-one (3 entities in total)
• Functional Keywords: ssgcid, metrs, methionyl-trna synthetase, protein biosynthesis, structural genomics, seattle structural genomics center for infectious disease, ligase, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Brucella suis biovar 1 (strain 1330)
• Cellular location: Cytoplasm : P59078
• Total number of polymer chains: 3
• Total formula weight: 182142.14

Authors

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2016-05-17, release date: 2016-05-25, Last modification date: 2023-09-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.45 Å)