3CJ4

Crystal structure of hepatitis c virus rna-dependent rna polymerase ns5b in complex with optimized small molecule fragments


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.07 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.215 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Fragment-based discovery of hepatitis C virus NS5b RNA polymerase inhibitors.

Antonysamy, S.S.Aubol, B.Blaney, J.Browner, M.F.Giannetti, A.M.Harris, S.F.Hebert, N.Hendle, J.Hopkins, S.Jefferson, E.Kissinger, C.Leveque, V.Marciano, D.McGee, E.Najera, I.Nolan, B.Tomimoto, M.Torres, E.Wright, T.

(2008) Bioorg Med Chem Lett 18: 2990-2995

  • DOI: https://doi.org/10.1016/j.bmcl.2008.03.056
  • Primary Citation of Related Structures:  
    3CIZ, 3CJ0, 3CJ2, 3CJ3, 3CJ4, 3CJ5

  • PubMed Abstract: 

    Non-nucleoside inhibitors of HCV NS5b RNA polymerase were discovered by a fragment-based lead discovery approach, beginning with crystallographic fragment screening. The NS5b binding affinity and biochemical activity of fragment hits and inhibitors was determined by surface plasmon resonance (Biacore) and an enzyme inhibition assay, respectively. Crystallographic fragment screening hits with approximately 1-10mM binding affinity (K(D)) were iteratively optimized to give leads with approximately 200nM biochemical activity and low microM cellular activity in a Replicon assay.


  • Organizational Affiliation

    Medicinal Chemistry, SGX Pharmaceuticals, Inc., 10505 Roselle Street, San Diego, CA 92121, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-directed RNA polymerase
A, B
576Hepatitis C virus subtype 1bMutation(s): 0 
Gene Names: NS5B
EC: 2.7.7.48
UniProt
Find proteins for P26663 (Hepatitis C virus genotype 1b (isolate BK))
Explore P26663 
Go to UniProtKB:  P26663
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP26663
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
SX5 Binding MOAD:  3CJ4 Kd: 310 (nM) from 1 assay(s)
PDBBind:  3CJ4 Kd: 310 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.07 Å
  • R-Value Free: 0.278 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.215 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.143α = 90
b = 86.259β = 93.31
c = 116.141γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-04-15
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2024-02-21
    Changes: Data collection, Database references, Derived calculations