1T45

STRUCTURAL BASIS FOR THE AUTOINHIBITION AND STI-571 INHIBITION OF C-KIT TYROSINE KINASE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


This is version 1.4 of the entry. See complete history


Literature

Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase.

Mol, C.D.Dougan, D.R.Schneider, T.R.Skene, R.J.Kraus, M.L.Scheibe, D.N.Snell, G.P.Zou, H.Sang, B.C.Wilson, K.P.

(2004) J Biol Chem 279: 31655-31663

  • DOI: https://doi.org/10.1074/jbc.M403319200
  • Primary Citation of Related Structures:  
    1T45, 1T46

  • PubMed Abstract: 

    The activity of the c-Kit receptor protein-tyrosine kinase is tightly regulated in normal cells, whereas deregulated c-Kit kinase activity is implicated in the pathogenesis of human cancers. The c-Kit juxtamembrane region is known to have an autoinhibitory function; however the precise mechanism by which c-Kit is maintained in an autoinhibited state is not known. We report the 1.9-A resolution crystal structure of native c-Kit kinase in an autoinhibited conformation and compare it with active c-Kit kinase. Autoinhibited c-Kit is stabilized by the juxtamembrane domain, which inserts into the kinase-active site and disrupts formation of the activated structure. A 1.6-A crystal structure of c-Kit in complex with STI-571 (Imatinib or Gleevec) demonstrates that inhibitor binding disrupts this natural mechanism for maintaining c-Kit in an autoinhibited state. Together, these results provide a structural basis for understanding c-Kit kinase autoinhibition and will facilitate the structure-guided design of specific inhibitors that target the activated and autoinhibited conformations of c-Kit kinase.


  • Organizational Affiliation

    Syrrx, Inc., San Diego, California, 92121, USA. clifford.mol@syrrx.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Homo sapiens v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog331Homo sapiensMutation(s): 0 
Gene Names: kit
EC: 2.7.1.112
UniProt & NIH Common Fund Data Resources
Find proteins for P10721 (Homo sapiens)
Explore P10721 
Go to UniProtKB:  P10721
PHAROS:  P10721
GTEx:  ENSG00000157404 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP10721
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.194 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.414α = 90
b = 77.23β = 90
c = 94.574γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
AMoREphasing
REFMACrefinement
HKL-2000data reduction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2004-06-15
    Type: Initial release
  • Version 1.1: 2008-04-30
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.3: 2017-08-23
    Changes: Refinement description, Source and taxonomy
  • Version 1.4: 2023-08-23
    Changes: Data collection, Database references, Refinement description