2WEV

Truncation and Optimisation of Peptide Inhibitors of CDK2, Cyclin A Through Structure Guided Design


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Truncation and Optimisation of Peptide Inhibitors of Cyclin-Dependent Kinase 2-Cyclin a Through Structure-Guided Design.

Kontopidis, G.Andrews, M.J.Mcinnes, C.Plater, A.Innes, L.Renachowski, S.Cowan, A.Fischer, P.M.

(2009) ChemMedChem 4: 1120

  • DOI: https://doi.org/10.1002/cmdc.200900093
  • Primary Citation of Related Structures:  
    2WEV, 2WFY, 2WHB

  • PubMed Abstract: 

    Peptides that inhibit cyclin-dependent kinase 2 by blocking the macromolecular substrate recruitment site of cyclin A were simplified, for example, by replacement of dipeptide units with beta-amino acids. The smallest inhibitor retaining activity was a tripeptide, whose binding mode was confirmed by X-ray crystallography. This result suggests that nonpeptidic cyclin groove inhibitors may be feasible therapeutic agents.The cyclin-dependent kinase 2-cyclin A complex is an important regulator of the DNA-synthesis phase of the mammalian cell cycle, which is frequently deregulated in cancer. Rather than blocking the ATP-binding site of the apparently redundant kinase subunit, targeting the binding site for macromolecular substrates and regulatory proteins of cyclin A represents a promising strategy to enforce tumour-selective apoptosis. The cyclin-binding groove can be blocked with comparatively small synthetic peptides, which indirectly leads to inhibition of kinase function, but these peptides are metabolically labile and membrane impermeable. As part of our ongoing effort to develop more druglike peptidomimetics derived from cyclin-groove-binding peptides, we report the results of our studies aimed at a detailed understanding of the structural determinants required for effective binding. Using a combination of peptide synthesis, biochemical assays and X-ray crystallography, we show that it is possible to simplify peptide structures through the replacement of dipeptide units in which one of the residues is not directly involved in binding, through the introduction of beta-amino acid residues that retain only the dipeptide residue side chain that is important for binding. This approach also allowed us to probe spatial constraints in general, as well as the importance of peptide backbone hydrogen-bonding functions. Our identification of potent beta-homoleucine-containing tetrapeptide inhibitors, as well as the finding that an optimised N-terminally acetylated tripeptide retains some cyclin A-binding affinity, suggest that the pharmacological targeting of the cyclin A binding groove may be feasible.


  • Organizational Affiliation

    Veterinary School, University of Thessaly, Karditsa 43100, Greece.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CELL DIVISION PROTEIN KINASE 2
A, C
298Homo sapiensMutation(s): 0 
EC: 2.7.1.37
UniProt & NIH Common Fund Data Resources
Find proteins for P24941 (Homo sapiens)
Explore P24941 
Go to UniProtKB:  P24941
PHAROS:  P24941
GTEx:  ENSG00000123374 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP24941
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLIN-A2
B, D
260Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P20248 (Homo sapiens)
Explore P20248 
Go to UniProtKB:  P20248
PHAROS:  P20248
GTEx:  ENSG00000145386 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP20248
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
ARG-ARG-B3L-MEA
E, F
6synthetic constructMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
CK7
Query on CK7

Download Ideal Coordinates CCD File 
G [auth A],
H [auth C]
[4-(2-AMINO-4-METHYL-THIAZOL-5-YL)-PYRIMIDIN-2-YL]-(3-NITRO-PHENYL)-AMINE
C14 H12 N6 O2 S
DYTKVFHLKPDNRW-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
MEA
Query on MEA
E, F
L-PEPTIDE LINKINGC10 H13 N O2PHE
Binding Affinity Annotations 
IDSourceBinding Affinity
CK7 BindingDB:  2WEV Ki: min: 2, max: 396 (nM) from 2 assay(s)
IC50: min: 10, max: 4400 (nM) from 2 assay(s)
PDBBind:  2WEV IC50: 10 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.190 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.523α = 90
b = 113.844β = 90
c = 158.462γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-06-09
    Type: Initial release
  • Version 1.1: 2017-02-08
    Changes: Derived calculations, Source and taxonomy, Version format compliance
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection, Database references, Derived calculations, Other
  • Version 2.1: 2023-12-13
    Changes: Refinement description