3MWW

Crystal structure of HCV NS5B polymerase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.219 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Importance of ligand bioactive conformation in the discovery of potent indole-diamide inhibitors of the hepatitis C virus NS5B.

LaPlante, S.R.Gillard, J.R.Jakalian, A.Aubry, N.Coulombe, R.Brochu, C.Tsantrizos, Y.S.Poirier, M.Kukolj, G.Beaulieu, P.L.

(2010) J Am Chem Soc 132: 15204-15212

  • DOI: https://doi.org/10.1021/ja101358s
  • Primary Citation of Related Structures:  
    3MWV, 3MWW

  • PubMed Abstract: 

    Significant advances have led to receptor induced-fit and conformational selection models for describing bimolecular recognition, but a more comprehensive view must evolve to also include ligand shape and conformational changes. Here, we describe an example where a ligand's "structural hinge" influences potency by inducing an "L-shape" bioactive conformation, and due to its solvent exposure in the complex, reasonable conformation-activity-relationships can be qualitatively attributed. From a ligand design perspective, this feature was exploited by successful linker hopping to an alternate "structural hinge" that led to a new and promising chemical series which matched the ligand bioactive conformation and the pocket bioactive space. Using a combination of X-ray crystallography, NMR and modeling with support from binding-site resistance mutant studies and photoaffinity labeling experiments, we were able to derive inhibitor-polymerase complexes for various chemical series.


  • Organizational Affiliation

    Department of Chemistry, Boehringer Ingelheim (Canada) Ltd., 2100 Cunard St., Laval, Quebec, Canada, H7S2G5. steven.laplante@boehringer-ingelheim.com


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: 2.7.7.48
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
Binding Affinity Annotations 
IDSourceBinding Affinity
BIW PDBBind:  3MWW IC50: 57 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.219 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 105.12α = 90
b = 106.55β = 90
c = 133.46γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
HKL-2000data reduction
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2010-10-27 
  • Deposition Author(s): Coulombe, R.

Revision History  (Full details and data files)

  • Version 1.0: 2010-10-27
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description