6GU7

CDK1/Cks2 in complex with AZD5438


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.229 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Differences in the Conformational Energy Landscape of CDK1 and CDK2 Suggest a Mechanism for Achieving Selective CDK Inhibition.

Wood, D.J.Korolchuk, S.Tatum, N.J.Wang, L.Z.Endicott, J.A.Noble, M.E.M.Martin, M.P.

(2019) Cell Chem Biol 26: 121-130.e5

  • DOI: https://doi.org/10.1016/j.chembiol.2018.10.015
  • Primary Citation of Related Structures:  
    6GU2, 6GU3, 6GU4, 6GU6, 6GU7, 6GUB, 6GUC, 6GUE, 6GUF, 6GUH, 6GUK

  • PubMed Abstract: 

    Dysregulation of the cell cycle characterizes many cancer subtypes, providing a rationale for developing cyclin-dependent kinase (CDK) inhibitors. Potent CDK2 inhibitors might target certain cancers in which CCNE1 is amplified. However, current CDK2 inhibitors also inhibit CDK1, generating a toxicity liability. We have used biophysical measurements and X-ray crystallography to investigate the ATP-competitive inhibitor binding properties of cyclin-free and cyclin-bound CDK1 and CDK2. We show that these kinases can readily be distinguished by such inhibitors when cyclin-free, but not when cyclin-bound. The basis for this discrimination is unclear from either inspection or molecular dynamics simulation of ligand-bound CDKs, but is reflected in the contacts made between the kinase N- and C-lobes. We conclude that there is a subtle but profound difference between the conformational energy landscapes of cyclin-free CDK1 and CDK2. The unusual properties of CDK1 might be exploited to differentiate CDK1 from other CDKs in future cancer therapeutic design.


  • Organizational Affiliation

    Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclin-dependent kinase 1
A, C, E, G
302Homo sapiensMutation(s): 0 
Gene Names: CDK1CDC2CDC28ACDKN1P34CDC2
EC: 2.7.11.22 (PDB Primary Data), 2.7.11.23 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for P06493 (Homo sapiens)
Explore P06493 
Go to UniProtKB:  P06493
PHAROS:  P06493
GTEx:  ENSG00000170312 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP06493
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclin-dependent kinases regulatory subunit 2
B, D, F, H
84Homo sapiensMutation(s): 0 
Gene Names: CKS2
UniProt
Find proteins for K9J4F7 (Desmodus rotundus)
Explore K9J4F7 
Go to UniProtKB:  K9J4F7
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupK9J4F7
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FB8 (Subject of Investigation/LOI)
Query on FB8

Download Ideal Coordinates CCD File 
I [auth A]4-(2-methyl-3-propan-2-yl-imidazol-4-yl)-~{N}-(4-methylsulfonylphenyl)pyrimidin-2-amine
C18 H21 N5 O2 S
WJRRGYBTGDJBFX-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
FB8 BindingDB:  6GU7 IC50: min: 16, max: 62 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.229 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.995α = 90
b = 149.202β = 92.23
c = 87.26γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
xia2data reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Medical Research Council (United Kingdom)United KingdomMR/N009738/1
Cancer Research UKUnited KingdomC2115/A21421

Revision History  (Full details and data files)

  • Version 1.0: 2018-12-05
    Type: Initial release
  • Version 1.1: 2018-12-26
    Changes: Data collection, Database references, Source and taxonomy, Structure summary
  • Version 1.2: 2019-01-30
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-17
    Changes: Data collection, Database references, Refinement description