2HAI

Crystal structure of HCV NS5B RNA polymerase in complex with novel class of dihydropyrone-containing inhibitor.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.215 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Identification and structure-based optimization of novel dihydropyrones as potent HCV RNA polymerase inhibitors.

Li, H.Tatlock, J.Linton, A.Gonzalez, J.Borchardt, A.Dragovich, P.Jewell, T.Prins, T.Zhou, R.Blazel, J.Parge, H.Love, R.Hickey, M.Doan, C.Shi, S.Duggal, R.Lewis, C.Fuhrman, S.

(2006) Bioorg Med Chem Lett 16: 4834-4838

  • DOI: https://doi.org/10.1016/j.bmcl.2006.06.065
  • Primary Citation of Related Structures:  
    2HAI

  • PubMed Abstract: 

    A novel class of non-nucleoside HCV NS5B polymerase inhibitors has been identified from screening. A co-crystal structure revealed an allosteric binding site in the protein that required a unique conformational change to accommodate inhibitor binding. Herein we report the structure-activity relationships (SARs) of this novel class of dihydropyrone-containing compounds that show potent inhibitory activities against the HCV RNA polymerase in biochemical assays.


  • Organizational Affiliation

    Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Dr., San Diego, CA 92121, USA. hui.li@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HEPATITIS C VIRUS NS5B RNA POLYMERASE576Hepacivirus hominisMutation(s): 5 
Gene Names: NS5B
EC: 2.7.7.48
UniProt
Find proteins for Q99AU2 (Hepatitis C virus subtype 1b)
Explore Q99AU2 
Go to UniProtKB:  Q99AU2
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ99AU2
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PFI
Query on PFI

Download Ideal Coordinates CCD File 
B [auth A](6S)-6-CYCLOPENTYL-6-[2-(3-FLUORO-4-ISOPROPOXYPHENYL)ETHYL]-4-HYDROXY-5,6-DIHYDRO-2H-PYRAN-2-ONE
C21 H27 F O4
AKNIHFDXRAOPAI-NRFANRHFSA-N
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
CME
Query on CME
A
L-PEPTIDE LINKINGC5 H11 N O3 S2CYS
CSD
Query on CSD
A
L-PEPTIDE LINKINGC3 H7 N O4 SCYS
Binding Affinity Annotations 
IDSourceBinding Affinity
PFI Binding MOAD:  2HAI IC50: 530 (nM) from 1 assay(s)
PDBBind:  2HAI IC50: 530 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.236 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.215 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 83.255α = 90
b = 83.255β = 90
c = 179.83γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-09-05
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations