1NVQ

The Complex Structure Of Checkpoint Kinase Chk1/UCN-01


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.206 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural Basis for Chk1 Inhibition by UCN-01

Zhao, B.Bower, M.J.McDevitt, P.J.Zhao, H.Davis, S.T.Johanson, K.O.Green, S.M.Concha, N.O.Zhou, B.B.

(2002) J Biol Chem 277: 46609-46615

  • DOI: https://doi.org/10.1074/jbc.M201233200
  • Primary Citation of Related Structures:  
    1NVQ, 1NVR, 1NVS

  • PubMed Abstract: 

    Chk1 is a serine-threonine kinase that plays an important role in the DNA damage response, including G(2)/M cell cycle control. UCN-01 (7-hydroxystaurosporine), currently in clinical trials, has recently been shown to be a potent Chk1 inhibitor that abrogates the G(2)/M checkpoint induced by DNA-damaging agents. To understand the structural basis of Chk1 inhibition by UCN-01, we determined the crystal structure of the Chk1 kinase domain in complex with UCN-01. Chk1 structures with staurosporine and its analog SB-218078 were also determined. All three compounds bind in the ATP-binding pocket of Chk1, producing only slight changes in the protein conformation. Selectivity of UCN-01 toward Chk1 over cyclin-dependent kinases can be explained by the presence of a hydroxyl group in the lactam moiety interacting with the ATP-binding pocket. Hydrophobic interactions and hydrogen-bonding interactions were observed in the structures between UCN-01 and the Chk1 kinase domain. The high structural complementarity of these interactions is consistent with the potency and selectivity of UCN-01.


  • Organizational Affiliation

    Department of Structural Biology, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase Chk1289Homo sapiensMutation(s): 0 
EC: 2.7.1
UniProt & NIH Common Fund Data Resources
Find proteins for O14757 (Homo sapiens)
Explore O14757 
Go to UniProtKB:  O14757
PHAROS:  O14757
GTEx:  ENSG00000149554 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO14757
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Peptide ASVSA5N/AMutation(s): 0 
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
UCN
Query on UCN

Download Ideal Coordinates CCD File 
D [auth A]7-HYDROXYSTAUROSPORINE
C28 H26 N4 O4
PBCZSGKMGDDXIJ-HQCWYSJUSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
UCN PDBBind:  1NVQ Ki: 5.6 (nM) from 1 assay(s)
BindingDB:  1NVQ Ki: 5.6 (nM) from 1 assay(s)
IC50: 9.9 (nM) from 1 assay(s)
Binding MOAD:  1NVQ Ki: 5.6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.206 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.022α = 90
b = 65.641β = 94.16
c = 57.865γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
X-PLORmodel building
CNSrefinement
HKL-2000data reduction
X-PLORphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-04-08
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-16
    Changes: Data collection, Database references, Derived calculations, Refinement description