6I4X

Crystal structure of SOCS2:Elongin C:Elongin B in complex with erythropoietin receptor peptide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.69 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.199 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Structural insights into substrate recognition by the SOCS2 E3 ubiquitin ligase.

Kung, W.W.Ramachandran, S.Makukhin, N.Bruno, E.Ciulli, A.

(2019) Nat Commun 10: 2534-2534

  • DOI: https://doi.org/10.1038/s41467-019-10190-4
  • Primary Citation of Related Structures:  
    6I4X, 6I5J, 6I5N

  • PubMed Abstract: 

    The suppressor of cytokine signaling 2 (SOCS2) acts as substrate recognition subunit of a Cullin5 E3 ubiquitin ligase complex. SOCS2 binds to phosphotyrosine-modified epitopes as degrons for ubiquitination and proteasomal degradation, yet the molecular basis of substrate recognition has remained elusive. Here, we report co-crystal structures of SOCS2-ElonginB-ElonginC in complex with phosphorylated peptides from substrates growth hormone receptor (GHR-pY595) and erythropoietin receptor (EpoR-pY426) at 1.98 Å and 2.69 Å, respectively. Both peptides bind in an extended conformation recapitulating the canonical SH2 domain-pY pose, but capture different conformations of the EF loop via specific hydrophobic interactions. The flexible BG loop is fully defined in the electron density, and does not contact the substrate degron directly. Cancer-associated SNPs located around the pY pocket weaken substrate-binding affinity in biophysical assays. Our findings reveal insights into substrate recognition and specificity by SOCS2, and provide a blueprint for small molecule ligand design.


  • Organizational Affiliation

    Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Elongin-BA [auth B]104Homo sapiensMutation(s): 0 
Gene Names: ELOBTCEB2
UniProt & NIH Common Fund Data Resources
Find proteins for Q15370 (Homo sapiens)
Explore Q15370 
Go to UniProtKB:  Q15370
PHAROS:  Q15370
GTEx:  ENSG00000103363 
Entity Groups  
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UniProt GroupQ15370
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Elongin-CB [auth C]97Homo sapiensMutation(s): 0 
Gene Names: ELOCTCEB1
UniProt & NIH Common Fund Data Resources
Find proteins for Q15369 (Homo sapiens)
Explore Q15369 
Go to UniProtKB:  Q15369
PHAROS:  Q15369
GTEx:  ENSG00000154582 
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UniProt GroupQ15369
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Suppressor of cytokine signaling 2C [auth A]169Homo sapiensMutation(s): 0 
Gene Names: SOCS2CIS2SSI2STATI2
UniProt & NIH Common Fund Data Resources
Find proteins for O14508 (Homo sapiens)
Explore O14508 
Go to UniProtKB:  O14508
PHAROS:  O14508
GTEx:  ENSG00000120833 
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UniProt GroupO14508
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  • Reference Sequence

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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Erythropoietin receptor11Homo sapiensMutation(s): 0 
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
PEG
Query on PEG

Download Ideal Coordinates CCD File 
E [auth A]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
CAS
Query on CAS
A [auth B]L-PEPTIDE LINKINGC5 H12 As N O2 SCYS
PTR
Query on PTR
D
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.69 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.199 
  • Space Group: I 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.287α = 90
b = 56.327β = 91.53
c = 203.392γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
Cootmodel building
AutoPROCdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European Research CouncilUnited KingdomERC-2012-StG-311460 DrugE3CRLs
United KingdomUniversity of Dundee, PhD Scholarship
Wellcome TrustUnited Kingdom100476/Z/12/Z
Wellcome TrustUnited Kingdom094090/Z/10/Z

Revision History  (Full details and data files)

  • Version 1.0: 2019-05-29
    Type: Initial release
  • Version 1.1: 2019-06-12
    Changes: Data collection, Structure summary
  • Version 1.2: 2019-06-19
    Changes: Data collection, Database references