5JM4

Crystal structure of 14-3-3zeta in complex with a cyclic peptide involving an adamantyl and a dicarboxy side chain


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.34 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.200 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structure-Based Design of Non-natural Macrocyclic Peptides That Inhibit Protein-Protein Interactions.

Kruger, D.M.Glas, A.Bier, D.Pospiech, N.Wallraven, K.Dietrich, L.Ottmann, C.Koch, O.Hennig, S.Grossmann, T.N.

(2017) J Med Chem 60: 8982-8988

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b01221
  • Primary Citation of Related Structures:  
    5JM4

  • PubMed Abstract: 

    Macrocyclic peptides can interfere with challenging biomolecular targets including protein-protein interactions. Whereas there are various approaches that facilitate the identification of peptide-derived ligands, their evolution into higher affinity binders remains a major hurdle. We report a virtual screen based on molecular docking that allows the affinity maturation of macrocyclic peptides taking non-natural amino acids into consideration. These macrocycles bear large and flexible substituents that usually complicate the use of docking approaches. A virtual library containing more than 1400 structures was screened against the target focusing on docking poses with the core structure resembling a known bioactive conformation. Based on this screen, a macrocyclic peptide 22 involving two non-natural amino acids was evolved showing increased target affinity and biological activity. Predicted binding modes were verified by X-ray crystallography. The presented workflow allows the screening of large macrocyclic peptides with diverse modifications thereby expanding the accessible chemical space and reducing synthetic efforts.


  • Organizational Affiliation

    Chemical Genomics Centre of the Max Planck Society , Otto-Hahn-Str. 15, 44227 Dortmund, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
14-3-3 protein zeta/delta
A, B
230Homo sapiensMutation(s): 0 
Gene Names: YWHAZ
UniProt & NIH Common Fund Data Resources
Find proteins for P63104 (Homo sapiens)
Explore P63104 
Go to UniProtKB:  P63104
PHAROS:  P63104
GTEx:  ENSG00000164924 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP63104
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
GLN-GLY-MKD-ANG-ASP-MKD-LEU-ASP-LEU-ALA-CLUC [auth D],
D [auth E]
11synthetic constructMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.34 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.200 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 84.92α = 90
b = 105.74β = 90
c = 113.93γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XSCALEdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
PHASERphasing

Structure Validation

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Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Emmy Noether programGermanyGR3592/2-1
German Research FoundationGermanySFB1093

Revision History  (Full details and data files)

  • Version 1.0: 2017-05-10
    Type: Initial release
  • Version 1.1: 2018-10-24
    Changes: Author supporting evidence, Data collection, Database references
  • Version 1.2: 2018-12-19
    Changes: Data collection, Derived calculations
  • Version 1.3: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description