8FP0

Ternary complex of CDK2 with small molecule ligands TW8672 and Roscovitine


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted RRCClick on this verticalbar to view detailsBest fitted 7TWClick on this verticalbar to view details

This is version 1.2 of the entry. See complete history


Literature

Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding.

Faber, E.B.Sun, L.Tang, J.Roberts, E.Ganeshkumar, S.Wang, N.Rasmussen, D.Majumdar, A.Hirsch, L.E.John, K.Yang, A.Khalid, H.Hawkinson, J.E.Levinson, N.M.Chennathukuzhi, V.Harki, D.A.Schonbrunn, E.Georg, G.I.

(2023) Nat Commun 14: 3213-3213

  • DOI: https://doi.org/10.1038/s41467-023-38732-x
  • Primary Citation of Related Structures:  
    7RWF, 7S84, 8FOW, 8FP0, 8FP5

  • PubMed Abstract: 

    Compared to most ATP-site kinase inhibitors, small molecules that target an allosteric pocket have the potential for improved selectivity due to the often observed lower structural similarity at these distal sites. Despite their promise, relatively few examples of structurally confirmed, high-affinity allosteric kinase inhibitors exist. Cyclin-dependent kinase 2 (CDK2) is a target for many therapeutic indications, including non-hormonal contraception. However, an inhibitor against this kinase with exquisite selectivity has not reached the market because of the structural similarity between CDKs. In this paper, we describe the development and mechanism of action of type III inhibitors that bind CDK2 with nanomolar affinity. Notably, these anthranilic acid inhibitors exhibit a strong negative cooperative relationship with cyclin binding, which remains an underexplored mechanism for CDK2 inhibition. Furthermore, the binding profile of these compounds in both biophysical and cellular assays demonstrate the promise of this series for further development into a therapeutic selective for CDK2 over highly similar kinases like CDK1. The potential of these inhibitors as contraceptive agents is seen by incubation with spermatocyte chromosome spreads from mouse testicular explants, where they recapitulate Cdk2 -/- and Spdya -/- phenotypes.


  • Organizational Affiliation

    Department of Medicinal Chemistry, University of Minnesota College of Pharmacy-Twin Cities, Minneapolis, MN, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cyclin-dependent kinase 2298Homo sapiensMutation(s): 0 
Gene Names: CDK2CDKN2
EC: 2.7.11.22
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
Binding Affinity Annotations 
IDSourceBinding Affinity
RRC BindingDB:  8FP0 Ki: 250 (nM) from 1 assay(s)
Kd: min: 2900, max: 3400 (nM) from 2 assay(s)
IC50: min: 0.52, max: 4600 (nM) from 24 assay(s)
7TW BindingDB:  8FP0 Kd: min: 1800, max: 4900 (nM) from 2 assay(s)
IC50: 4600 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.82α = 90
b = 72.1β = 90
c = 72.5γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHENIXphasing

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 RRCClick on this verticalbar to view detailsBest fitted 7TWClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not fundedUnited States--

Revision History  (Full details and data files)

  • Version 1.0: 2023-05-31
    Type: Initial release
  • Version 1.1: 2023-06-14
    Changes: Database references
  • Version 1.2: 2023-10-25
    Changes: Data collection