3JVS

Characterization of the Chk1 allosteric inhibitor binding site


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.187 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Characterization of the CHK1 allosteric inhibitor binding site.

Vanderpool, D.Johnson, T.O.Ping, C.Bergqvist, S.Alton, G.Phonephaly, S.Rui, E.Luo, C.Deng, Y.L.Grant, S.Quenzer, T.Margosiak, S.Register, J.Brown, E.Ermolieff, J.

(2009) Biochemistry 48: 9823-9830

  • DOI: https://doi.org/10.1021/bi900258v
  • Primary Citation of Related Structures:  
    3JVR, 3JVS

  • PubMed Abstract: 

    Checkpoint kinase 1 (CHK1) is a key element in the DNA damage response pathway and plays a crucial role in the S-G(2)-phase checkpoint. Inhibiting CHK1 is a therapeutic strategy involving abrogation of the G2/M mitotic checkpoint defense of tumor cells toward lethal damage induced by DNA-directed chemotherapeutic agents. To date, most CHK1 inhibition approaches have involved targeting the ATP site of this kinase. In this study, we provide crystallographic and kinetic characterization of two small molecule inhibitors that bind to an allosteric site in the proximity of the CHK1 substrate site. Analysis of kinetic and biophysical data has led to the conclusion that these small molecule allosteric site inhibitors of CHK1 are reversible and are neither ATP- nor peptide substrate-competitive. K(i) values of 1.89 and 0.15 microM, respectively, have been determined for these compounds using a mixed inhibitor kinetic analysis. Cocrystal structures of the inhibitors bound to CHK1 reveal an allosteric site, unique to CHK1, located in the C-terminal domain and consisting of a shallow groove linked to a small hydrophobic pocket. The pocket displays induced fit characteristics in the presence of the two inhibitors. These findings establish the potential for the development of highly selective CHK1 inhibitors.


  • Organizational Affiliation

    Department of Biochemistry and Primary Screening, Pfizer, La Jolla, San Diego 92121, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase Chk1271Homo sapiensMutation(s): 0 
Gene Names: CHEK1CHK1
EC: 2.7.11.1
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
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AGY
Query on AGY

Download Ideal Coordinates CCD File 
B [auth A]2-[(4-tert-butyl-3-nitrophenyl)carbonyl]-N-naphthalen-1-ylhydrazinecarboxamide
C22 H22 N4 O4
YZMKNNITNHTADN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
AGY Binding MOAD:  3JVS Kd: 290 (nM) from 1 assay(s)
PDBBind:  3JVS Kd: 290 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.187 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.754α = 90
b = 65.578β = 93.73
c = 57.931γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
CNSrefinement
CNXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-10-06 
  • Deposition Author(s): Chen, P.

Revision History  (Full details and data files)

  • Version 1.0: 2009-10-06
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-06-07
    Changes: Source and taxonomy
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations