3K54

Structures of human Bruton's tyrosine kinase in active and inactive conformations suggests a mechanism of activation for TEC family kinases.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.94 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.202 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases.

Marcotte, D.J.Liu, Y.T.Arduini, R.M.Hession, C.A.Miatkowski, K.Wildes, C.P.Cullen, P.F.Hong, V.Hopkins, B.T.Mertsching, E.Jenkins, T.J.Romanowski, M.J.Baker, D.P.Silvian, L.F.

(2010) Protein Sci 19: 429-439

  • DOI: https://doi.org/10.1002/pro.321
  • Primary Citation of Related Structures:  
    3GEN, 3K54

  • PubMed Abstract: 

    Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, plays a crucial role in B-cell maturation and mast cell activation. Although the structures of the unphosphorylated mouse BTK kinase domain and the unphosphorylated and phosphorylated kinase domains of human ITK are known, understanding the kinase selectivity profiles of BTK inhibitors has been hampered by the lack of availability of a high resolution, ligand-bound BTK structure. Here, we report the crystal structures of the human BTK kinase domain bound to either Dasatinib (BMS-354825) at 1.9 A resolution or to 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolospyrimidin- 7-yl-cyclopentane at 1.6 A resolution. This data provides information relevant to the development of small molecule inhibitors targeting BTK and the TEC family of nonreceptor tyrosine kinases. Analysis of the structural differences between the TEC and Src families of kinases near the Trp-Glu-Ile motif in the N-terminal region of the kinase domain suggests a mechanism of regulation of the TEC family members.


  • Organizational Affiliation

    Biogen Idec, Inc., Drug Discovery Department, 12 Cambridge Center, Cambridge, Massachusetts 02142, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase BTK283Homo sapiensMutation(s): 1 
Gene Names: AGMX1ATKBPKBTK
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q06187 (Homo sapiens)
Explore Q06187 
Go to UniProtKB:  Q06187
PHAROS:  Q06187
GTEx:  ENSG00000010671 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ06187
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1N1
Query on 1N1

Download Ideal Coordinates CCD File 
B [auth A]N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE
C22 H26 Cl N7 O2 S
ZBNZXTGUTAYRHI-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1N1 PDBBind:  3K54 Kd: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.94 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.202 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73.438α = 90
b = 104.622β = 90
c = 38.107γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2010-01-19
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Refinement description, Version format compliance
  • Version 1.2: 2021-10-13
    Changes: Database references, Derived calculations
  • Version 1.3: 2023-09-06
    Changes: Data collection, Refinement description