4HGE

JAK2 kinase (JH1 domain) in complex with compound 8


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.182 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.

Hanan, E.J.van Abbema, A.Barrett, K.Blair, W.S.Blaney, J.Chang, C.Eigenbrot, C.Flynn, S.Gibbons, P.Hurley, C.A.Kenny, J.R.Kulagowski, J.Lee, L.Magnuson, S.R.Morris, C.Murray, J.Pastor, R.M.Rawson, T.Siu, M.Ultsch, M.Zhou, A.Sampath, D.Lyssikatos, J.P.

(2012) J Med Chem 55: 10090-10107

  • DOI: https://doi.org/10.1021/jm3012239
  • Primary Citation of Related Structures:  
    4HGE

  • PubMed Abstract: 

    The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.


  • Organizational Affiliation

    Department of Discovery Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK2
A, B
300Homo sapiensMutation(s): 0 
Gene Names: JAK2
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for O60674 (Homo sapiens)
Explore O60674 
Go to UniProtKB:  O60674
PHAROS:  O60674
GTEx:  ENSG00000096968 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60674
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
15V
Query on 15V

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N-[1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
C17 H13 Cl N6 O
YLBXBHSEZZNJPX-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A, B
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
15V BindingDB:  4HGE Ki: min: 11.9, max: 12 (nM) from 2 assay(s)
Binding MOAD:  4HGE Ki: 11.9 (nM) from 1 assay(s)
PDBBind:  4HGE Ki: 11.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.182 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 111.898α = 90
b = 111.898β = 90
c = 70.572γ = 90
Software Package:
Software NamePurpose
BOSdata collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-10-24
    Type: Initial release
  • Version 1.1: 2012-12-12
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.3: 2023-12-06
    Changes: Data collection