3PHX

OTU Domain of Crimean Congo Hemorrhagic Fever Virus in complex with ISG15


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.142 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Molecular basis for ubiquitin and ISG15 cross-reactivity in viral ovarian tumor domains.

Akutsu, M.Ye, Y.Virdee, S.Chin, J.W.Komander, D.

(2011) Proc Natl Acad Sci U S A 108: 2228-2233

  • DOI: https://doi.org/10.1073/pnas.1015287108
  • Primary Citation of Related Structures:  
    3PHU, 3PHW, 3PHX

  • PubMed Abstract: 

    Crimean Congo hemorrhagic fever virus (CCHFV) is a deadly human pathogen that evades innate immune responses by efficiently interfering with antiviral signaling pathways mediated by NF-κB, IRF3, and IFNα/β. These pathways rely on protein ubiquitination for their activation, and one outcome is the modification of proteins with the ubiquitin (Ub)-like modifier interferon-stimulated gene (ISG)15. CCHFV and related viruses encode a deubiquitinase (DUB) of the ovarian tumor (OTU) family, which unlike eukaryotic OTU DUBs also targets ISG15 modifications. Here we characterized the viral OTU domain of CCHFV (vOTU) biochemically and structurally, revealing that it hydrolyzes four out of six tested Ub linkages, but lacks activity against linear and K29-linked Ub chains. vOTU cleaved Ub and ISG15 with similar kinetics, and we were able to understand vOTU cross-reactivity at the molecular level from crystal structures of vOTU in complex with Ub and ISG15. An N-terminal extension in vOTU not present in eukaryotic OTU binds to the hydrophobic Ile44 patch of Ub, which results in a dramatically different Ub orientation compared to a eukaryotic OTU-Ub complex. The C-terminal Ub-like fold of ISG15 (ISG15-C) adopts an equivalent binding orientation. Interestingly, ISG15-C contains an additional second hydrophobic surface that is specifically contacted by vOTU. These subtle differences in Ub/ISG15 binding allowed the design of vOTU variants specific for either Ub or ISG15, which will be useful tools to understand the relative contribution of ubiquitination vs. ISGylation in viral infection. Furthermore, the crystal structures will allow structure-based design of antiviral agents targeting this enzyme.


  • Organizational Affiliation

    Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-directed RNA polymerase L185Crimean-Congo hemorrhagic fever virus strain IbAr10200Mutation(s): 0 
Gene Names: L
EC: 3.4.19.12 (PDB Primary Data), 2.7.7.48 (PDB Primary Data)
UniProt
Find proteins for Q6TQR6 (Crimean-Congo hemorrhagic fever virus (strain Nigeria/IbAr10200/1970))
Explore Q6TQR6 
Go to UniProtKB:  Q6TQR6
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ6TQR6
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Ubiquitin-like protein ISG1579Homo sapiensMutation(s): 0 
Gene Names: ISG15G1P2UCRP
UniProt & NIH Common Fund Data Resources
Find proteins for P05161 (Homo sapiens)
Explore P05161 
Go to UniProtKB:  P05161
PHAROS:  P05161
GTEx:  ENSG00000187608 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP05161
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
F [auth A]
G [auth A]
C [auth A],
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
N [auth B],
O [auth B],
P [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
ACY
Query on ACY

Download Ideal Coordinates CCD File 
L [auth A],
Q [auth B]
ACETIC ACID
C2 H4 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-N
NEH
Query on NEH

Download Ideal Coordinates CCD File 
M [auth B]ETHANAMINE
C2 H7 N
QUSNBJAOOMFDIB-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.192 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.142 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.52α = 90
b = 37.1β = 94.24
c = 84.35γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-02-02
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2014-08-06
    Changes: Database references