7F9A

Homo sapiens Prolyl-tRNA Synthetase (HsPRS) in Complex with L-proline and compound L97


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Targeting prolyl-tRNA synthetase via a series of ATP-mimetics to accelerate drug discovery against toxoplasmosis.

Yogavel, M.Bougdour, A.Mishra, S.Malhotra, N.Chhibber-Goel, J.Bellini, V.Harlos, K.Laleu, B.Hakimi, M.A.Sharma, A.

(2023) PLoS Pathog 19: e1011124-e1011124

  • DOI: https://doi.org/10.1371/journal.ppat.1011124
  • Primary Citation of Related Structures:  
    7F98, 7F99, 7F9A, 7F9B, 7F9C, 7F9D, 7FAK, 7FAL, 7FAM, 7FAN, 7VC1, 7VC2, 7VC3

  • PubMed Abstract: 

    The prolyl-tRNA synthetase (PRS) is a validated drug target for febrifugine and its synthetic analog halofuginone (HFG) against multiple apicomplexan parasites including Plasmodium falciparum and Toxoplasma gondii. Here, a novel ATP-mimetic centered on 1-(pyridin-4-yl) pyrrolidin-2-one (PPL) scaffold has been validated to bind to Toxoplasma gondii PRS and kill toxoplasma parasites. PPL series exhibited potent inhibition at the cellular (T. gondii parasites) and enzymatic (TgPRS) levels compared to the human counterparts. Cell-based chemical mutagenesis was employed to determine the mechanism of action via a forward genetic screen. Tg-resistant parasites were analyzed with wild-type strain by RNA-seq to identify mutations in the coding sequence conferring drug resistance by computational analysis of variants. DNA sequencing established two mutations, T477A and T592S, proximal to terminals of the PPL scaffold and not directly in the ATP, tRNA, or L-pro sites, as supported by the structural data from high-resolution crystal structures of drug-bound enzyme complexes. These data provide an avenue for structure-based activity enhancement of this chemical series as anti-infectives.


  • Organizational Affiliation

    Molecular Medicine-Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi, India.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bifunctional glutamate/proline--tRNA ligase
A, B
505Homo sapiensMutation(s): 0 
Gene Names: EPRS1EPRSGLNSPARSQARSQPRSPIG32
EC: 6.1.1.17 (PDB Primary Data), 6.1.1.15 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P07814 (Homo sapiens)
Explore P07814 
Go to UniProtKB:  P07814
PHAROS:  P07814
GTEx:  ENSG00000136628 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP07814
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1XK (Subject of Investigation/LOI)
Query on 1XK

Download Ideal Coordinates CCD File 
C [auth A],
P [auth B]
4-[(3S)-3-cyclopropyl-3-(hydroxymethyl)-2-oxidanylidene-pyrrolidin-1-yl]-N-[[3-fluoranyl-5-(1-methylpyrazol-4-yl)phenyl]methyl]-6-methyl-pyridine-2-carboxamide
C26 H28 F N5 O3
SGTQLZKTLHEFII-AREMUKBSSA-N
PRO
Query on PRO

Download Ideal Coordinates CCD File 
O [auth A],
U [auth B]
PROLINE
C5 H9 N O2
ONIBWKKTOPOVIA-BYPYZUCNSA-N
ZN (Subject of Investigation/LOI)
Query on ZN

Download Ideal Coordinates CCD File 
D [auth A],
Q [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CA (Subject of Investigation/LOI)
Query on CA

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth A]
I [auth A]
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
M [auth A],
R [auth B],
S [auth B],
T [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
CL (Subject of Investigation/LOI)
Query on CL

Download Ideal Coordinates CCD File 
K [auth A],
L [auth A],
N [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.74α = 90
b = 105.92β = 90
c = 145.38γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
Aimlessdata scaling
Auto-Rickshawphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2022-10-05
    Type: Initial release
  • Version 1.1: 2023-04-19
    Changes: Database references
  • Version 1.2: 2023-11-29
    Changes: Data collection, Refinement description