PDBsum entry 4py2

Ligase/ligase inhibitor

PDB id: 4py2

Contents

Protein chains

495 a.a.

Ligands

43E ×3

EDO ×7

Waters ×551

PDB id:

4py2

Name:

Ligase/ligase inhibitor

Title:

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

Structure:

Methionine--tRNA ligase. Chain: a, b, c. Synonym: methionyl-tRNA synthetase. Engineered: yes

Source:

Brucella melitensis. Organism_taxid: 359391. Strain: 2308. Gene: metg, bab1_1014. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.15Å R-factor: 0.179 R-free: 0.212

Authors:

Seattle Structural Genomics Center For Infectious Disease (Ssgcid)

Key ref:

K.K.Ojo et al. (2016). Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis. Plos One, 11, e0160350. PubMed id: 27500735 DOI: 10.1371/journal.pone.0160350

Date:

25-Mar-14 Release date: 15-Apr-15

Protein chains

Q2YQ76  (Q2YQ76_BRUA2) -  Methionine--tRNA ligase from Brucella abortus (strain 2308)

Seq: 515 a.a.

Struc: 495 a.a.

Enzyme reactions

• Enzyme class: E.C.6.1.1.10 - methionine--tRNA ligase.
• Reaction: tRNA(Met) + L-methionine + ATP = L-methionyl-tRNA(Met) + AMP + diphosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1371/journal.pone.0160350

Plos One 11:e0160350 (2016)

PubMed id: 27500735

Brucella melitensis Methionyl-tRNA-Synthetase (MetRS), a Potential Drug Target for Brucellosis.

K.K.Ojo, R.M.Ranade, Z.Zhang, D.M.Dranow, J.B.Myers, R.Choi, S.Nakazawa Hewitt, T.E.Edwards, D.R.Davies, D.Lorimer, S.M.Boyle, L.K.Barrett, F.S.Buckner, E.Fan, W.C.Van Voorhis.

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.