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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.179 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

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

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.

(2016) PLoS One 11: e0160350-e0160350

  • DOI: https://doi.org/10.1371/journal.pone.0160350
  • Primary Citation of Related Structures:  
    4DLP, 4PY2, 5K0S, 5K0T

  • 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.


  • Organizational Affiliation

    Center for Emerging and Re-emerging Infectious Diseases (CERID), Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Washington, United States of America.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Methionine--tRNA ligase
A, B, C
536Brucella abortus 2308Mutation(s): 0 
Gene Names: metGBAB1_1014
EC: 6.1.1.10
UniProt
Find proteins for Q2YQ76 (Brucella abortus (strain 2308))
Explore Q2YQ76 
Go to UniProtKB:  Q2YQ76
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ2YQ76
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
43E
Query on 43E

Download Ideal Coordinates CCD File 
D [auth A],
F [auth B],
K [auth C]
1-{3-[(3,5-dichlorobenzyl)amino]propyl}-3-thiophen-3-ylurea
C15 H17 Cl2 N3 O S
DGBJLEREWKGWML-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
E [auth A]
G [auth B]
H [auth B]
I [auth B]
J [auth B]
E [auth A],
G [auth B],
H [auth B],
I [auth B],
J [auth B],
L [auth C],
M [auth C]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
43E Binding MOAD:  4PY2 IC50: 272 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.179 
  • Space Group: P 1
  • Diffraction Data: https://doi.org/10.18430/M34PY2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.01α = 110.47
b = 99.48β = 87.24
c = 104γ = 99.99
Software Package:
Software NamePurpose
XSCALEdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2015-04-15
    Type: Initial release
  • Version 1.1: 2016-08-17
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Refinement description
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description