4JTW

Crystal structure of HCV NS5B polymerase in complex with coupound 1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.200 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Molecular Dynamics Simulations and Structure-Based Rational Design Lead to Allosteric HCV NS5B Polymerase Thumb Pocket 2 Inhibitor with Picomolar Cellular Replicon Potency.

Hucke, O.Coulombe, R.Bonneau, P.Bertrand-Laperle, M.Brochu, C.Gillard, J.Joly, M.A.Landry, S.Lepage, O.Llinas-Brunet, M.Pesant, M.Poirier, M.Poirier, M.McKercher, G.Marquis, M.Kukolj, G.Beaulieu, P.L.Stammers, T.A.

(2014) J Med Chem 57: 1932-1943

  • DOI: https://doi.org/10.1021/jm4004522
  • Primary Citation of Related Structures:  
    4JTW, 4JTY, 4JTZ, 4JU1, 4JU2

  • PubMed Abstract: 

    The design and preliminary SAR of a new series of 1H-quinazolin-4-one (QAZ) allosteric HCV NS5B thumb pocket 2 (TP-2) inhibitors was recently reported. To support optimization efforts, a molecular dynamics (MD) based modeling workflow was implemented, providing information on QAZ binding interactions with NS5B. This approach predicted a small but critical ligand-binding induced movement of a protein backbone region which increases the pocket size and improves access to the backbone carbonyl groups of Val 494 and Pro 495. This localized backbone shift was consistent with key SAR results and was subsequently confirmed by X-ray crystallography. The MD protocol guided the design of inhibitors, exploiting novel H-bond interactions with the two backbone carbonyl groups, leading to the first thumb pocket 2 NS5B inhibitor with picomolar antiviral potency in genotype (gt) 1a and 1b replicons (EC50 = 120 and 110 pM, respectively) and with EC50 ≤ 80 nM against gt 2-6.


  • Organizational Affiliation

    Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Genome polyprotein
A, B
576Hepatitis C virus isolate HC-J4Mutation(s): 0 
Gene Names: NS5B
EC: 3.4.22 (PDB Primary Data), 3.4.21.98 (PDB Primary Data), 3.6.1.15 (PDB Primary Data), 3.6.4.13 (PDB Primary Data), 2.7.7.48 (PDB Primary Data)
UniProt
Find proteins for O92972 (Hepatitis C virus genotype 1b (strain HC-J4))
Explore O92972 
Go to UniProtKB:  O92972
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO92972
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1NU
Query on 1NU

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B]
1-(2,4,6-trifluorobenzyl)-6-[2-(trifluoromethyl)phenoxy]quinazolin-4(1H)-one
C22 H12 F6 N2 O2
SELQSCGULJIZPA-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
I [auth B],
J [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.200 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 106.43α = 90
b = 108β = 90
c = 134.92γ = 90
Software Package:
Software NamePurpose
MAR345dtbdata collection
CNXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
CNXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2013-07-10 
  • Deposition Author(s): Coulombe, R.

Revision History  (Full details and data files)

  • Version 1.0: 2013-07-10
    Type: Initial release
  • Version 1.1: 2014-03-26
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description