4WI1

Crystal Structure of Prolyl-tRNA synthetase (ProRS, Proline--tRNA ligase) from Plasmodium falciparum in complex with TCMDC-124506


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.162 
  • R-Value Observed: 0.162 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase.

Nakazawa Hewitt, S.Dranow, D.M.Horst, B.G.Abendroth, J.A.Forte, B.Hallyburton, I.Jansen, C.Baragana, B.Choi, R.Rivas, K.L.Hulverson, M.A.Dumais, M.Edwards, T.E.Lorimer, D.D.Fairlamb, A.H.Gray, D.W.Read, K.D.Lehane, A.M.Kirk, K.Myler, P.J.Wernimont, A.Walpole, C.S.Stacy, R.Barrett, L.K.Gilbert, I.H.Van Voorhis, W.C.

(2016) ACS Infect Dis 

  • DOI: https://doi.org/10.1021/acsinfecdis.6b00078
  • Primary Citation of Related Structures:  
    4NCX, 4Q15, 4WI1, 5IFU

  • PubMed Abstract: 

    Plasmodium falciparum (Pf) prolyl-tRNA synthetase (ProRS) is one of the few chemical-genetically validated drug targets for malaria, yet highly selective inhibitors have not been described. In this paper, approximately 40,000 compounds were screened to identify compounds that selectively inhibit PfProRS enzyme activity versus Homo sapiens (Hs) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of PfProRS. We identified two new inhibitors of PfProRS that bind outside the active site. These two allosteric inhibitors showed >100 times specificity for PfProRS compared to HsProRS, demonstrating this class of compounds could overcome the toxicity related to HsProRS inhibition by halofuginone and its analogues. Initial medicinal chemistry was performed on one of the two compounds, guided by the cocrystallography of the compound with PfProRS, and the results can instruct future medicinal chemistry work to optimize these promising new leads for drug development against malaria.


  • Organizational Affiliation

    Center for Emerging and Reemerging Infectious Disease (CERID), University of Washington , 750 Republican Street, Seattle, Washington 98109, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proline--tRNA ligase
A, B
506Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: proRSPFL0670c
EC: 6.1.1.15
UniProt
Find proteins for Q8I5R7 (Plasmodium falciparum (isolate 3D7))
Explore Q8I5R7 
Go to UniProtKB:  Q8I5R7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8I5R7
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3O6
Query on 3O6

Download Ideal Coordinates CCD File 
C [auth A],
N [auth B]
1-(4-fluorophenyl)-3-[4-(4-fluorophenyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea
C18 H13 F5 N4 O
BJWCFFZTMUBHLH-UHFFFAOYSA-N
IMD
Query on IMD

Download Ideal Coordinates CCD File 
L [auth A],
V [auth B]
IMIDAZOLE
C3 H5 N2
RAXXELZNTBOGNW-UHFFFAOYSA-O
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
G [auth A]
H [auth A]
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
O [auth B],
P [auth B],
Q [auth B],
R [auth B],
S [auth B],
T [auth B],
U [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
M [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
MG
Query on MG

Download Ideal Coordinates CCD File 
K [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3O6 Binding MOAD:  4WI1 IC50: 5000 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

Unit Cell:
Length ( Å )Angle ( ˚ )
a = 148.18α = 90
b = 91.34β = 129.53
c = 110.91γ = 90
Software Package:
Software NamePurpose
ARPmodel building
PHENIXrefinement
PDB_EXTRACTdata extraction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-05-04
    Type: Initial release
  • Version 1.1: 2016-11-16
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Advisory, Derived calculations, Refinement description
  • Version 1.3: 2023-09-27
    Changes: Advisory, Data collection, Database references, Refinement description