4H1M

Crystal structure of PYK2 with the indole 10c


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.296 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.226 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Identification of novel series of pyrazole and indole-urea based DFG-out PYK2 inhibitors.

Bhattacharya, S.K.Aspnes, G.E.Bagley, S.W.Boehm, M.Brosius, A.D.Buckbinder, L.Chang, J.S.Dibrino, J.Eng, H.Frederick, K.S.Griffith, D.A.Griffor, M.C.Guimaraes, C.R.Guzman-Perez, A.Han, S.Kalgutkar, A.S.Klug-McLeod, J.Garcia-Irizarry, C.Li, J.Lippa, B.Price, D.A.Southers, J.A.Walker, D.P.Wei, L.Xiao, J.Zawistoski, M.P.Zhao, X.

(2012) Bioorg Med Chem Lett 22: 7523-7529

  • DOI: https://doi.org/10.1016/j.bmcl.2012.10.039
  • Primary Citation of Related Structures:  
    4H1J, 4H1M

  • PubMed Abstract: 

    Previous drug discovery efforts identified classical PYK2 kinase inhibitors such as 2 and 3 that possess selectivity for PYK2 over its intra-family isoform FAK. Efforts to identify more kinome-selective chemical matter that stabilize a DFG-out conformation of the enzyme are described herein. Two sub-series of PYK2 inhibitors, an indole carboxamide-urea and a pyrazole-urea have been identified and found to have different binding interactions with the hinge region of PYK2. These leads proved to be more selective than the original classical inhibitors.


  • Organizational Affiliation

    Worldwide Medicinal Chemistry, Pfizer Global Research and Development, 620 Memorial Drive, Cambridge, MA 02139, United States. samit.k.bhattacharya@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protein-tyrosine kinase 2-beta293Homo sapiensMutation(s): 0 
Gene Names: PTK2BFAK2PYK2RAFTK
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
0YJ
Query on 0YJ

Download Ideal Coordinates CCD File 
B [auth A]7-({[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]carbamoyl}amino)-N-(propan-2-yl)-1H-indole-2-carboxamide
C27 H32 N6 O2
WGABQSVUYBMTBW-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0YJ PDBBind:  4H1M IC50: 78 (nM) from 1 assay(s)
BindingDB:  4H1M IC50: min: 78, max: 530 (nM) from 2 assay(s)
Binding MOAD:  4H1M IC50: 78 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.99 Å
  • R-Value Free: 0.296 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.226 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.393α = 90
b = 81.429β = 90
c = 86.396γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
PHASERphasing
BUSTERrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2012-11-28 
  • Deposition Author(s): Han, S.

Revision History  (Full details and data files)

  • Version 1.0: 2012-11-28
    Type: Initial release
  • Version 1.1: 2012-12-12
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations