4Y95

Crystal structure of the kinase domain of Bruton's tyrosine kinase with mutations in the activation loop

  • Classification: TRANSFERASE
  • Organism(s): Bos taurus
  • Expression System: Escherichia coli
  • Mutation(s): Yes 

  • Deposited: 2015-02-16 Released: 2015-03-18 
  • Deposition Author(s): Wang, Q., Rosen, C.E., Kuriyan, J.
  • Funding Organization(s): National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID), Howard Hughes Medical Institute (HHMI), Cancer Research Institute

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.155 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history. 


Literature

Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate.

Wang, Q., Vogan, E.M., Nocka, L.M., Rosen, C.E., Zorn, J.A., Harrison, S.C., Kuriyan, J.

(2015) Elife 4

  • DOI: https://doi.org/10.7554/eLife.06074
  • Primary Citation of Related Structures:  
    4XI2, 4Y93, 4Y94, 4Y95

  • PubMed Abstract: 

    Bruton's tyrosine kinase (Btk), a Tec-family tyrosine kinase, is essential for B-cell function. We present crystallographic and biochemical analyses of Btk, which together reveal molecular details of its autoinhibition and activation. Autoinhibited Btk adopts a compact conformation like that of inactive c-Src and c-Abl. A lipid-binding PH-TH module, unique to Tec kinases, acts in conjunction with the SH2 and SH3 domains to stabilize the inactive conformation. In addition to the expected activation of Btk by membranes containing phosphatidylinositol triphosphate (PIP3), we found that inositol hexakisphosphate (IP6), a soluble signaling molecule found in both animal and plant cells, also activates Btk. This activation is a consequence of a transient PH-TH dimerization induced by IP6, which promotes transphosphorylation of the kinase domains. Sequence comparisons with other Tec-family kinases suggest that activation by IP6 is unique to Btk.

    • Organizational Affiliation: 

    Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Non-specific protein-tyrosine kinase
A, B, C, D
266Bos taurusMutation(s): 9 
Gene Names: BTK
EC: 2.7.10.2
UniProt
Find proteins for Q3ZC95 (Bos taurus)
Explore Q3ZC95 
Go to UniProtKB:  Q3ZC95
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ3ZC95
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
746
Query on 746
Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
M [auth C],
Q [auth D]		4-tert-butyl-N-[2-methyl-3-(4-methyl-6-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]benzamide
C34 H37 N5 O4
JIFCFQDXHMUPGP-UHFFFAOYSA-N
PE4
Query on PE4
Download Ideal Coordinates CCD File 
L [auth B],
P [auth C]		2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL
C16 H34 O8
PJWQOENWHPEPKI-UHFFFAOYSA-N
GOL
Query on GOL
Download Ideal Coordinates CCD File 
F [auth A]
I [auth B]
J [auth B]
N [auth C]
R [auth D]
F [auth A],
I [auth B],
J [auth B],
N [auth C],
R [auth D],
S [auth D],
T [auth D],
U [auth D]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
BME
Query on BME
Download Ideal Coordinates CCD File 
G [auth A],
K [auth B],
O [auth C]		BETA-MERCAPTOETHANOL
C2 H6 O S
DGVVWUTYPXICAM-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
746 BindingDB:  4Y95 Kd: 1.5 (nM) from 1 assay(s)
IC50: min: 0.61, max: 150 (nM) from 5 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.155 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.929α = 90.73
b = 79.067β = 89.9
c = 79.178γ = 89.99
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data scaling
PDB_EXTRACTdata extraction
HKL-2000data reduction

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History & Funding Information

Deposition Data

Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)United StatesAI 091580
Howard Hughes Medical Institute (HHMI)United States--
Cancer Research InstituteUnited States--

Revision History  (Full details and data files)

  • Version 1.0: 2015-03-18
    Type: Initial release
  • Version 1.1: 2017-09-27
    Changes: Advisory, Author supporting evidence, Derived calculations, Source and taxonomy
  • Version 1.2: 2019-11-20
    Changes: Author supporting evidence
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references