3FZS

Crystal Structure of PYK2 complexed with BIRB796


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural characterization of proline-rich tyrosine kinase 2 (PYK2) reveals a unique (DFG-out) conformation and enables inhibitor design.

Han, S.Mistry, A.Chang, J.S.Cunningham, D.Griffor, M.Bonnette, P.C.Wang, H.Chrunyk, B.A.Aspnes, G.E.Walker, D.P.Brosius, A.D.Buckbinder, L.

(2009) J Biol Chem 284: 13193-13201

  • DOI: https://doi.org/10.1074/jbc.M809038200
  • Primary Citation of Related Structures:  
    3FZO, 3FZP, 3FZR, 3FZS, 3FZT

  • PubMed Abstract: 

    Proline-rich tyrosine kinase 2 (PYK2) is a cytoplasmic, non-receptor tyrosine kinase implicated in multiple signaling pathways. It is a negative regulator of osteogenesis and considered a viable drug target for osteoporosis treatment. The high-resolution structures of the human PYK2 kinase domain with different inhibitor complexes establish the conventional bilobal kinase architecture and show the conformational variability of the DFG loop. The basis for the lack of selectivity for the classical kinase inhibitor, PF-431396, within the FAK family is explained by our structural analyses. Importantly, the novel DFG-out conformation with two diarylurea inhibitors (BIRB796, PF-4618433) reveals a distinct subclass of non-receptor tyrosine kinases identifiable by the gatekeeper Met-502 and the unique hinge loop conformation of Leu-504. This is the first example of a leucine residue in the hinge loop that blocks the ATP binding site in the DFG-out conformation. Our structural, biophysical, and pharmacological studies suggest that the unique features of the DFG motif, including Leu-504 hinge-loop variability, can be exploited for the development of selective protein kinase inhibitors.


  • Organizational Affiliation

    Pfizer Global Research & Development, Groton, CT 06340, USA. seungil.han@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protein tyrosine kinase 2 beta277Homo sapiensMutation(s): 0 
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q14289 (Homo sapiens)
Explore Q14289 
Go to UniProtKB:  Q14289
PHAROS:  Q14289
GTEx:  ENSG00000120899 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ14289
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
B96
Query on B96

Download Ideal Coordinates CCD File 
B [auth A]1-(5-TERT-BUTYL-2-P-TOLYL-2H-PYRAZOL-3-YL)-3-[4-(2-MORPHOLIN-4-YL-ETHOXY)-NAPHTHALEN-1-YL]-UREA
C31 H37 N5 O3
MVCOAUNKQVWQHZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
B96 BindingDB:  3FZS Kd: 990 (nM) from 1 assay(s)
IC50: min: 400, max: 1.15e+4 (nM) from 3 assay(s)
Binding MOAD:  3FZS IC50: 1500 (nM) from 1 assay(s)
PDBBind:  3FZS IC50: 1500 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.192 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.503α = 90
b = 81.694β = 90
c = 87.256γ = 90
Software Package:
Software NamePurpose
REFMACrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-03-31 
  • Deposition Author(s): Han, S.

Revision History  (Full details and data files)

  • Version 1.0: 2009-03-31
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2024-02-21
    Changes: Data collection, Database references, Derived calculations