4I33

Crystal structure of HCV NS3/4A R155K protease complexed with compound 4


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Molecular Mechanism by Which a Potent Hepatitis C Virus NS3-NS4A Protease Inhibitor Overcomes Emergence of Resistance.

O'Meara, J.A.Lemke, C.T.Godbout, C.Kukolj, G.Lagace, L.Moreau, B.Thibeault, D.White, P.W.Llinas-Brunet, M.

(2013) J Biol Chem 288: 5673-5681

  • DOI: https://doi.org/10.1074/jbc.M112.439455
  • Primary Citation of Related Structures:  
    4I31, 4I32, 4I33

  • PubMed Abstract: 

    Although optimizing the resistance profile of an inhibitor can be challenging, it is potentially important for improving the long term effectiveness of antiviral therapy. This work describes our rational approach toward the identification of a macrocyclic acylsulfonamide that is a potent inhibitor of the NS3-NS4A proteases of all hepatitis C virus genotypes and of a panel of genotype 1-resistant variants. The enhanced potency of this compound versus variants D168V and R155K facilitated x-ray determination of the inhibitor-variant complexes. In turn, these structural studies revealed a complex molecular basis of resistance and rationalized how such compounds are able to circumvent these mechanisms.


  • Organizational Affiliation

    Boehringer Ingelheim (Canada) Limited, Research and Development, Laval, Quebec H7S 2G5, Canada. RESGeneral.lav@boehringer-ingelheim.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Genome polyprotein
A, B
187Hepatitis C virus (isolate Japanese)Mutation(s): 1 
Gene Names: POLG_HCVJA
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 P26662 (Hepatitis C virus genotype 1b (isolate Japanese))
Explore P26662 
Go to UniProtKB:  P26662
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP26662
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
HCV non-structural protein 4A
C, D
17Hepatitis C virus (isolate Japanese)Mutation(s): 0 
UniProt
Find proteins for P26662 (Hepatitis C virus genotype 1b (isolate Japanese))
Explore P26662 
Go to UniProtKB:  P26662
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP26662
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1BV
Query on 1BV

Download Ideal Coordinates CCD File 
F [auth A],
H [auth B]
(2R,6S,7E,10E,13aR,14aR,16aS)-2-{[7-methoxy-8-methyl-2-(propan-2-yloxy)quinolin-4-yl]oxy}-N-[(1-methylcyclopropyl)sulfonyl]-6-{[(1-methyl-1H-pyrazol-3-yl)carbonyl]amino}-5,16-dioxo-1,2,3,6,9,12,13,13a,14,15,16,16a-dodecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide
C41 H51 N7 O9 S
ZHIQOLBHZJFLCW-QVARATBXSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
E [auth A],
G [auth B]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.216 
  • R-Value Observed: 0.218 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.527α = 90
b = 93.527β = 90
c = 81.449γ = 120
Software Package:
Software NamePurpose
MAR345dtbdata collection
PHENIXmodel building
PHENIXrefinement
d*TREKdata reduction
d*TREKdata scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2013-01-02 
  • Deposition Author(s): Lemke, C.T.

Revision History  (Full details and data files)

  • Version 1.0: 2013-01-02
    Type: Initial release
  • Version 1.1: 2013-01-09
    Changes: Database references
  • Version 1.2: 2013-03-13
    Changes: Database references