5X94

Crystal structure of SHP2_SH2-CagA EPIYA_D peptide complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.163 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Differential Mechanisms for SHP2 Binding and Activation Are Exploited by Geographically Distinct Helicobacter pylori CagA Oncoproteins.

Hayashi, T.Senda, M.Suzuki, N.Nishikawa, H.Ben, C.Tang, C.Nagase, L.Inoue, K.Senda, T.Hatakeyama, M.

(2017) Cell Rep 20: 2876-2890

  • DOI: https://doi.org/10.1016/j.celrep.2017.08.080
  • Primary Citation of Related Structures:  
    5X7B, 5X94

  • PubMed Abstract: 

    Helicobacter pylori East Asian CagA is more closely associated with gastric cancer than Western CagA. Here we show that, upon tyrosine phosphorylation, the East Asian CagA-specific EPIYA-D segment binds to the N-SH2 domain of pro-oncogenic SHP2 phosphatase two orders of magnitude greater than Western CagA-specific EPIYA-C. This high-affinity binding is achieved via cryptic interaction between Phe at the +5 position from phosphotyrosine in EPIYA-D and a hollow on the N-SH2 phosphopeptide-binding floor. Also, duplication of EPIYA-C in Western CagA, which increases gastric cancer risk, enables divalent high-affinity binding with SHP2 via N-SH2 and C-SH2. These strong CagA bindings enforce enzymatic activation of SHP2, which endows cells with neoplastic traits. Mechanistically, N-SH2 in SHP2 is in an equilibrium between stimulatory "relaxed" and inhibitory "squeezed" states, which is fixed upon high-affinity CagA binding to the "relaxed" state that stimulates SHP2. Accordingly, East Asian CagA and Western CagA exploit distinct mechanisms for SHP2 deregulation.


  • Organizational Affiliation

    Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein phosphatase non-receptor type 11
A, B
220Homo sapiensMutation(s): 0 
Gene Names: PTPN11PTP2CSHPTP2
EC: 3.1.3.48
UniProt & NIH Common Fund Data Resources
Find proteins for Q06124 (Homo sapiens)
Explore Q06124 
Go to UniProtKB:  Q06124
PHAROS:  Q06124
GTEx:  ENSG00000179295 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ06124
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Cag pathogenicity island proteinC [auth L],
D [auth M],
E [auth N],
F [auth O]
13Helicobacter pylori F32Mutation(s): 0 
UniProt
Find proteins for P55980 (Helicobacter pylori (strain ATCC 700392 / 26695))
Explore P55980 
Go to UniProtKB:  P55980
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP55980
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
MSE
Query on MSE
A, B
L-PEPTIDE LINKINGC5 H11 N O2 SeMET
PTR
Query on PTR
C [auth L],
D [auth M],
E [auth N],
F [auth O]
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.157 
  • R-Value Observed: 0.163 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 28.184α = 90
b = 121.968β = 101.26
c = 72.171γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-09-13
    Type: Initial release
  • Version 1.1: 2017-10-18
    Changes: Database references
  • Version 1.2: 2023-11-22
    Changes: Data collection, Database references, Refinement description