2OC7

Structure of Hepatitis C Viral NS3 protease domain complexed with NS4A peptide and ketoamide SCH571696


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.293 
  • R-Value Work: 0.193 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of the HCV NS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization.

Prongay, A.J.Guo, Z.Yao, N.Pichardo, J.Fischmann, T.Strickland, C.Myers Jr., J.Weber, P.C.Beyer, B.M.Ingram, R.Hong, Z.Prosise, W.W.Ramanathan, L.Taremi, S.S.Yarosh-Tomaine, T.Zhang, R.Senior, M.Yang, R.S.Malcolm, B.Arasappan, A.Bennett, F.Bogen, S.L.Chen, K.Jao, E.Liu, Y.T.Lovey, R.G.Saksena, A.K.Venkatraman, S.Girijavallabhan, V.Njoroge, F.G.Madison, V.

(2007) J Med Chem 50: 2310-2318

  • DOI: https://doi.org/10.1021/jm060173k
  • Primary Citation of Related Structures:  
    2O8M, 2OBO, 2OBQ, 2OC0, 2OC1, 2OC7, 2OC8

  • PubMed Abstract: 

    The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets [the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249-264]. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease that is currently in clinical trials.


  • Organizational Affiliation

    Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. andrew.prongay@spcorp.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Hepatitis C Virus
A, C
200Hepacivirus hominisMutation(s): 0 
Gene Names: NS3
UniProt
Find proteins for P27958 (Hepatitis C virus genotype 1a (isolate H77))
Explore P27958 
Go to UniProtKB:  P27958
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27958
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Hepatitis C Virus
B, D
23Hepatitis C virus genotype 1a (isolate H77)Mutation(s): 0 
UniProt
Find proteins for P27958 (Hepatitis C virus genotype 1a (isolate H77))
Explore P27958 
Go to UniProtKB:  P27958
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27958
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HU4
Query on HU4

Download Ideal Coordinates CCD File 
G [auth A]TERT-BUTYL {(1S)-2-[(1R,2S,5R)-2-({[(1S)-3-AMINO-1-(CYCLOBUTYLMETHYL)-2,3-DIOXOPROPYL]AMINO}CARBONYL)-7,7-DIMETHYL-6-OXA-3-AZABICYCLO[3.2.0]HEPT-3-YL]-1-CYCLOHEXYL-2-OXOETHYL}CARBAMATE
C29 H46 N4 O7
WRVVRHORVNXEJF-YFNVTMOMSA-N
BME
Query on BME

Download Ideal Coordinates CCD File 
F [auth A]BETA-MERCAPTOETHANOL
C2 H6 O S
DGVVWUTYPXICAM-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A],
H [auth C]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
HU4 PDBBind:  2OC7 Ki: 1400 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.293 
  • R-Value Work: 0.193 
  • Space Group: H 3 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 224.676α = 90
b = 224.676β = 90
c = 75.604γ = 120
Software Package:
Software NamePurpose
ADSCdata collection
X-PLORmodel building
X-PLORrefinement
HKL-2000data reduction
SCALEPACKdata scaling
X-PLORphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2007-07-31
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.2: 2012-02-22
    Changes: Structure summary
  • Version 1.3: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description