1RGQ

M9A HCV Protease complex with pentapeptide keto-amide inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.312 
  • R-Value Work: 0.279 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Hepatitis C NS3 protease inhibition by peptidyl-alpha-ketoamide inhibitors: kinetic mechanism and structure.

Liu, Y.Stoll, V.S.Richardson, P.L.Saldivar, A.Klaus, J.L.Molla, A.Kohlbrenner, W.Kati, W.M.

(2004) Arch Biochem Biophys 421: 207-216

  • DOI: https://doi.org/10.1016/j.abb.2003.11.013
  • Primary Citation of Related Structures:  
    1RGQ

  • PubMed Abstract: 

    A series of novel peptidyl-alpha-ketoamide compounds were evaluated as inhibitors of the deltaNS3-NS4A serine protease from the hepatitis C virus. These peptidyl-alpha-ketoamide inhibitors with Ki values ranging from 0.17 nM to 5.6 microM exhibited slow-binding inhibition. Kinetic studies established one-step kinetic mechanisms and dissociation rate constants in the 3-7 x 10(-5) s(-1) range for these compounds. The association rate constants, which ranged from 10 to 263,000 M(-1) s(-1), were responsible for the greater than four order of magnitude overall binding affinity range exhibited by this series. An X-ray crystal structure of a protease-inhibitor complex revealed an unusual interaction between the oxyanion of the adduct and the protein as well as a significant movement in the S1' region of the protein loop comprising residues 35-42. These results are quite different from peptidyl-alpha-ketoacid inhibition of HCV protease, which reportedly undergoes no notable conformational changes and proceeds with a two-step slow-binding kinetic mechanism.


  • Organizational Affiliation

    Antiviral Research, Infectious Disease Research and Advanced Technology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6217, USA. yaya.liu@abbott.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
NS3 Protease
A, B
200Hepacivirus hominisMutation(s): 0 
EC: 3.4.21.98
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
NS4A peptide
C, D
22N/AMutation(s): 0 
UniProt
Find proteins for O39914 (Hepacivirus hominis)
Explore O39914 
Go to UniProtKB:  O39914
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO39914
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AKP
Query on AKP

Download Ideal Coordinates CCD File 
G [auth B]N-(PYRAZIN-2-YLCARBONYL)LEUCYLISOLEUCYL-N~1~-{1-[2-({1-CARBOXY-2-[4-(PHOSPHONOOXY)PHENYL]ETHYL}AMINO)-1,1-DIHYDROXY-2-OXOETHYL]BUT-3-ENYL}-3-CYCLOHEXYLALANINAMIDE
C41 H60 N7 O13 P
NANINTGNSYDVAR-PBWGIQFFSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A],
F [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.312 
  • R-Value Work: 0.279 
  • Space Group: H 3 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 226.385α = 90
b = 226.385β = 90
c = 76.864γ = 120
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
CNXrefinement
HKL-2000data reduction
CNXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-10-19
    Type: Initial release
  • Version 1.1: 2007-10-16
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance