1G3N

STRUCTURE OF A P18(INK4C)-CDK6-K-CYCLIN TERNARY COMPLEX


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.228 

wwPDB Validation   3D Report Full Report


This is version 1.5 of the entry. See complete history


Literature

Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors.

Jeffrey, P.D.Tong, L.Pavletich, N.P.

(2000) Genes Dev 14: 3115-3125

  • DOI: https://doi.org/10.1101/gad.851100
  • Primary Citation of Related Structures:  
    1G3N

  • PubMed Abstract: 

    The cyclin-dependent kinases 4 and 6 (Cdk4/6) that drive progression through the G(1) phase of the cell cycle play a central role in the control of cell proliferation, and CDK deregulation is a frequent event in cancer. Cdk4/6 are regulated by the D-type cyclins, which bind to CDKs and activate the kinase, and by the INK4 family of inhibitors. INK4 proteins can bind both monomeric CDK, preventing its association with a cyclin, and also the CDK-cyclin complex, forming an inactive ternary complex. In vivo, binary INK4-Cdk4/6 complexes are more abundant than ternary INK4-Cdk4/6-cyclinD complexes, and it has been suggested that INK4 binding may lead to the eventual dissociation of the cyclin. Here we present the 2.9-A crystal structure of the inactive ternary complex between Cdk6, the INK4 inhibitor p18(INK4c), and a D-type viral cyclin. The structure reveals that p18(INK4c) inhibits the CDK-cyclin complex by distorting the ATP binding site and misaligning catalytic residues. p18(INK4c) also distorts the cyclin-binding site, with the cyclin remaining bound at an interface that is substantially reduced in size. These observations support the model that INK4 binding weakens the cyclin's affinity for the CDK. This structure also provides insights into the specificity of the D-type cyclins for Cdk4/6.


  • Organizational Affiliation

    Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLIN-DEPENDENT KINASE 6A,
D [auth E]
326Homo sapiensMutation(s): 0 
Gene Names: CYCLIN-DEPENDENT KINASE 6
EC: 2.7.1.37
UniProt & NIH Common Fund Data Resources
Find proteins for Q00534 (Homo sapiens)
Explore Q00534 
Go to UniProtKB:  Q00534
PHAROS:  Q00534
GTEx:  ENSG00000105810 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ00534
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLIN-DEPENDENT KINASE 6 INHIBITORB,
E [auth F]
168Homo sapiensMutation(s): 0 
Gene Names: P18(INK4C)
UniProt & NIH Common Fund Data Resources
Find proteins for P42773 (Homo sapiens)
Explore P42773 
Go to UniProtKB:  P42773
PHAROS:  P42773
GTEx:  ENSG00000123080 
Entity Groups  
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UniProt GroupP42773
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
V-CYCLINC,
F [auth G]
257Human gammaherpesvirus 8Mutation(s): 0 
Gene Names: K-CYCLIN (VIRAL CYCLIND HOMOLOG)
UniProt
Find proteins for Q98147 (Human herpesvirus 8)
Explore Q98147 
Go to UniProtKB:  Q98147
Entity Groups  
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UniProt GroupQ98147
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.262 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.228 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.78α = 90
b = 146.95β = 90
c = 164.82γ = 90
Software Package:
Software NamePurpose
AMoREphasing
CNSrefinement
SCALEPACKdata scaling

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2001-01-10
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-10-04
    Changes: Refinement description
  • Version 1.4: 2018-04-04
    Changes: Data collection
  • Version 1.5: 2024-02-07
    Changes: Data collection, Database references