6YPL

14-3-3 sigma with RelA/p65 binding site pS45 and covalently bound TCF521-037


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Fragment-Based Stabilizers of Protein-Protein Interactions through Imine-Based Tethering.

Wolter, M.Valenti, D.Cossar, P.J.Levy, L.M.Hristeva, S.Genski, T.Hoffmann, T.Brunsveld, L.Tzalis, D.Ottmann, C.

(2020) Angew Chem Int Ed Engl 59: 21520-21524

  • DOI: https://doi.org/10.1002/anie.202008585
  • Primary Citation of Related Structures:  
    6YOW, 6YOX, 6YOY, 6YP2, 6YP3, 6YP8, 6YPL, 6YPY, 6YQ2

  • PubMed Abstract: 

    Small-molecule stabilization of protein-protein interactions (PPIs) is a promising concept in drug discovery, however the question how to identify or design chemical starting points in a "bottom-up" approach is largely unanswered. We report a novel concept for identifying initial chemical matter for PPI stabilization based on imine-forming fragments. The imine bond offers a covalent anchor for site-directed fragment targeting, whereas its transient nature enables efficient analysis of structure-activity relationships. This bond enables fragment identification and optimisation using protein crystallography. We report novel fragments that bind specifically to a lysine at the PPI interface of the p65-subunit-derived peptide of NF-κB with the adapter protein 14-3-3. Those fragments that subsequently establish contacts with the p65-derived peptide, rather than with 14-3-3, efficiently stabilize the 14-3-3/p65 complex and offer novel starting points for molecular glues.


  • Organizational Affiliation

    Laboratory of Chemical Biology, Department of Biomedical, Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB, Eindhoven, The Netherlands.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
14-3-3 protein sigma236Homo sapiensMutation(s): 0 
Gene Names: SFNHME1
UniProt & NIH Common Fund Data Resources
Find proteins for P31947 (Homo sapiens)
Explore P31947 
Go to UniProtKB:  P31947
PHAROS:  P31947
GTEx:  ENSG00000175793 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP31947
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
p65pS45B [auth P]13Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q04206 (Homo sapiens)
Explore Q04206 
Go to UniProtKB:  Q04206
PHAROS:  Q04206
GTEx:  ENSG00000173039 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ04206
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
CSO
Query on CSO
A
L-PEPTIDE LINKINGC3 H7 N O3 SCYS
SEP
Query on SEP
B [auth P]L-PEPTIDE LINKINGC3 H8 N O6 PSER
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.667α = 90
b = 112.708β = 90
c = 62.765γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
MOLREPphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
DIALSdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
European CommissionEuropean Union675179

Revision History  (Full details and data files)

  • Version 1.0: 2020-09-23
    Type: Initial release
  • Version 1.1: 2020-10-07
    Changes: Database references
  • Version 1.2: 2020-12-16
    Changes: Database references
  • Version 1.3: 2024-01-24
    Changes: Data collection, Database references, Refinement description
  • Version 1.4: 2024-11-20
    Changes: Structure summary