1OS5

Crystal structure of HCV NS5B RNA polymerase complexed with a novel non-competitive inhibitor.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.201 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

Crystallographic identification of a noncompetitive inhibitor binding site on the hepatitis C virus NS5B RNA polymerase enzyme.

Love, R.A.Parge, H.E.Yu, X.Hickey, M.J.Diehl, W.Gao, J.Wriggers, H.Ekker, A.Wang, L.Thomson, J.A.Dragovich, P.S.Fuhrman, S.A.

(2003) J Virol 77: 7575-7581

  • DOI: https://doi.org/10.1128/jvi.77.13.7575-7581.2003
  • Primary Citation of Related Structures:  
    1OS5

  • PubMed Abstract: 

    The virus-encoded nonstructural protein 5B (NS5B) of hepatitis C virus (HCV) is an RNA-dependent RNA polymerase and is absolutely required for replication of the virus. NS5B exhibits significant differences from cellular polymerases and therefore has become an attractive target for anti-HCV therapy. Using a high-throughput screen, we discovered a novel NS5B inhibitor that binds to the enzyme noncompetitively with respect to nucleotide substrates. Here we report the crystal structure of NS5B complexed with this small molecule inhibitor. Unexpectedly, the inhibitor is bound within a narrow cleft on the protein's surface in the "thumb" domain, about 30 A from the enzyme's catalytic center. The interaction between this inhibitor and NS5B occurs without dramatic changes to the structure of the protein, and sequence analysis suggests that the binding site is conserved across known HCV genotypes. Possible mechanisms of inhibition include perturbation of protein dynamics, interference with RNA binding, and disruption of enzyme oligomerization.


  • Organizational Affiliation

    Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 92121, USA. robert.love@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Hepatitis C virus NS5B RNA polymerase576Hepatitis C virus subtype 1bMutation(s): 3 
Gene Names: NS5B
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
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NH1
Query on NH1

Download Ideal Coordinates CCD File 
B [auth A]3-(4-AMINO-2-TERT-BUTYL-5-METHYL-PHENYLSULFANYL)-6-CYCLOPENTYL-4-HYDROXY-6-[2-(4-HYDROXY-PHENYL)-ETHYL]-5,6-DIHYDRO-PYRAN-2-ONE
C29 H37 N O4 S
ZEBFKFGJWHOOST-LJAQVGFWSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
NH1 Binding MOAD:  1OS5 Kd: 140 (nM) from 1 assay(s)
PDBBind:  1OS5 Kd: 140 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.201 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 83α = 90
b = 83β = 90
c = 180γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
X-PLORrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-03-18
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Source and taxonomy, Version format compliance
  • Version 1.3: 2021-02-03
    Changes: Database references, Derived calculations
  • Version 1.4: 2021-10-27
    Changes: Database references
  • Version 1.5: 2024-02-14
    Changes: Data collection