5A14

Human CDK2 with type II inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.197 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Type II Inhibitors Targeting Cdk2.

Alexander, L.T.Mobitz, H.Drueckes, P.Savitsky, P.Fedorov, O.Elkins, J.M.Deane, C.M.Cowan-Jacob, S.W.Knapp, S.

(2015) ACS Chem Biol 10: 2116

  • DOI: https://doi.org/10.1021/acschembio.5b00398
  • Primary Citation of Related Structures:  
    5A14

  • PubMed Abstract: 

    Kinases can switch between active and inactive conformations of the ATP/Mg(2+) binding motif DFG, which has been explored for the development of type I or type II inhibitors. However, factors modulating DFG conformations remain poorly understood. We chose CDK2 as a model system to study the DFG in-out transition on a target that was thought to have an inaccessible DFG-out conformation. We used site-directed mutagenesis of key residues identified in structural comparisons in conjunction with biochemical and biophysical characterization of the generated mutants. As a result, we identified key residues that facilitate the DFG-out movement, facilitating binding of type II inhibitors. However, surprisingly, we also found that wild type CDK2 is able to bind type II inhibitors. Using protein crystallography structural analysis of the CDK2 complex with an aminopyrimidine-phenyl urea inhibitor (K03861) revealed a canonical type II binding mode and the first available type II inhibitor CDK2 cocrystal structure. We found that the identified type II inhibitors compete with binding of activating cyclins. In addition, analysis of the binding kinetics of the identified inhibitors revealed slow off-rates. The study highlights the importance of residues that may be distant to the ATP binding pocket in modulating the energetics of the DFG-out transition and hence inhibitor binding. The presented data also provide the foundation for a new class of slow off-rate cyclin-competitive CDK2 inhibitors targeting the inactive DFG-out state of this important kinase target.


  • Organizational Affiliation

    Structural Genomics Consortium, University of Oxford , Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLIN-DEPENDENT KINASE 2299Homo sapiensMutation(s): 1 
EC: 2.7.11.22 (PDB Primary Data), 2.7.11.1 (PDB Primary Data)
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
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LQ5
Query on LQ5

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
1-[4-(2-azanylpyrimidin-4-yl)oxyphenyl]-3-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]urea
C24 H26 F3 N7 O2
PWDLXPJQFNVTNL-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
LQ5 BindingDB:  5A14 Kd: min: 9.7, max: 53 (nM) from 5 assay(s)
IC50: min: 800, max: 1.00e+4 (nM) from 4 assay(s)
-TΔS: min: -6.11e+1, max: 1683.7 (kJ/mol) from 12 assay(s)
ΔH: min: -7.61e+1, max: -1.56e+1 (kJ/mol) from 12 assay(s)
ΔG: min: -4.44e+1, max: -2.73e+1 (kJ/mol) from 12 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.197 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.41α = 90
b = 67.27β = 90
c = 89.13γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-22
    Type: Initial release
  • Version 1.1: 2015-12-16
    Changes: Database references
  • Version 1.2: 2019-10-23
    Changes: Data collection, Database references, Derived calculations, Other