RCSB PDB - 7O5D: 14-3-3 sigma with RelA/p65 binding site pS45 and covalently bound TCF521-160

 7O5D

14-3-3 sigma with RelA/p65 binding site pS45 and covalently bound TCF521-160


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.174 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

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This is version 1.3 of the entry. See complete history


Literature

An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-kappa B-Utilizing a Reversible Covalent Tethering Approach.

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

(2021) J Med Chem 64: 8423-8436

  • DOI: https://doi.org/10.1021/acs.jmedchem.1c00401
  • Primary Citation of Related Structures:  
    7BI3, 7BIQ, 7BIW, 7BIY, 7BJB, 7BJF, 7BJL, 7BJW, 7BKH, 7NJ9, 7NJB, 7NK3, 7NK5, 7NLA, 7NLE, 7NM1, 7NM3, 7NM9, 7NMH, 7NR7, 7NV4, 7NVI, 7NWS, 7NXS, 7NXT, 7NXW, 7NXY, 7NY4, 7NYE, 7NYF, 7NYG, 7NZ6, 7NZG, 7NZK, 7NZV, 7O34, 7O3A, 7O3F, 7O3P, 7O3Q, 7O3R, 7O3S, 7O57, 7O59, 7O5A, 7O5C, 7O5D, 7O5F, 7O5G, 7O5O

  • PubMed Abstract: 

    Protein-protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein-protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks established methodologies for drug design. Here, we report the systematic ″bottom-up″ development of a reversible covalent PPI stabilizer. An imine bond was employed to anchor the stabilizer at the interface of the 14-3-3/p65 complex, leading to a molecular glue that elicited an 81-fold increase in complex stabilization. Utilizing protein crystallography and biophysical assays, we deconvoluted how chemical properties of a stabilizer translate to structural changes in the ternary 14-3-3/p65/molecular glue complex. Furthermore, we explore how this leads to high cooperativity and increased stability of the complex.


  • Organizational Affiliation

    Department of Biomedical Engineering, Laboratory of Chemical Biology 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
Transcription factor p65B [auth P]13Homo sapiensMutation(s): 1 
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
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
V2W (Subject of Investigation/LOI)
Query on V2W

Download Ideal Coordinates CCD File 
D [auth A]4-methanoyl-~{N}-[(4-methoxyphenyl)methyl]benzamide
C16 H15 N O3
SCOZUTCGYBXUCE-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth P]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A],
F [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
MG
Query on MG

Download Ideal Coordinates CCD File 
E [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
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: 0.205 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.174 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.742α = 90
b = 112.517β = 90
c = 62.63γ = 90
Software Package:
Software NamePurpose
Aimlessdata scaling
MOLREPphasing
PHENIXrefinement
PDB_EXTRACTdata extraction
DIALSdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted V2WClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
H2020 Marie Curie Actions of the European CommissionEuropean Union675179

Revision History  (Full details and data files)

  • Version 1.0: 2021-06-09
    Type: Initial release
  • Version 1.1: 2021-07-07
    Changes: Database references
  • Version 1.2: 2024-01-31
    Changes: Data collection, Database references, Refinement description
  • Version 1.3: 2024-10-09
    Changes: Structure summary