3KQL

Three Conformational Snapshots of the Hepatitis C Virus NS3 Helicase Reveal a Ratchet Translocation Mechanism


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.184 

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This is version 1.3 of the entry. See complete history


Literature

Three conformational snapshots of the hepatitis C virus NS3 helicase reveal a ratchet translocation mechanism.

Gu, M.Rice, C.M.

(2010) Proc Natl Acad Sci U S A 107: 521-528

  • DOI: https://doi.org/10.1073/pnas.0913380107
  • Primary Citation of Related Structures:  
    3KQH, 3KQK, 3KQL, 3KQN, 3KQU

  • PubMed Abstract: 

    A virally encoded superfamily-2 (SF2) helicase (NS3h) is essential for the replication of hepatitis C virus, a leading cause of liver disease worldwide. Efforts to elucidate the function of NS3h and to develop inhibitors against it, however, have been hampered by limited understanding of its molecular mechanism. Here we show x-ray crystal structures for a set of NS3h complexes, including ground-state and transition-state ternary complexes captured with ATP mimics (ADP.BeF(3) and ). These structures provide, for the first time, three conformational snapshots demonstrating the molecular basis of action for a SF2 helicase. Upon nucleotide binding, overall domain rotation along with structural transitions in motif V and the bound DNA leads to the release of one base from the substrate base-stacking row and the loss of several interactions between NS3h and the 3' DNA segment. As nucleotide hydrolysis proceeds into the transition state, stretching of a "spring" helix and another overall conformational change couples rearrangement of the (d)NTPase active site to additional hydrogen-bonding between NS3h and DNA. Together with biochemistry, these results demonstrate a "ratchet" mechanism involved in the unidirectional translocation and define the step size of NS3h as one base per nucleotide hydrolysis cycle. These findings suggest feasible strategies for developing specific inhibitors to block the action of this attractive, yet largely unexplored drug target.


  • Organizational Affiliation

    Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065, USA. mgu@rockefeller.edu


Macromolecules

Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine protease/NTPase/helicase NS3
A, B
437Hepatitis C virus (isolate Con1)Mutation(s): 0 
Gene Names: NS3
EC: 3.4.21.98 (PDB Primary Data), 3.6.1.15 (PDB Primary Data), 3.6.1 (PDB Primary Data)
UniProt
Find proteins for Q9WMX2 (Hepatitis C virus genotype 1b (isolate Con1))
Explore Q9WMX2 
Go to UniProtKB:  Q9WMX2
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9WMX2
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains LengthOrganismImage
5'-D(*TP*TP*TP*TP*TP*T)-3'C [auth E],
D [auth F]
6N/A
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.211 
  • R-Value Work: 0.184 
  • Space Group: P 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.535α = 90
b = 75.315β = 90.16
c = 144.229γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
CNSrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-01-26
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations