5CF6

CRYSTAL STRUCTURE OF JANUS KINASE 2 IN COMPLEX WITH N,N-DICYCLOPROPYL-10-[(2S)-2,3-DIHYDROXYPROPYL]-3-METHYL-7-(METHYLAMINO)-3,5,8,10-TETRAAZATRICYCLO [7.3.0.02,6]DODECA-1(9),2(6),4,7,11-PENTAENE-11-CARBOXAMIDE

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.187 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors.

Hart, A.C., Schroeder, G.M., Wan, H., Grebinski, J., Inghrim, J., Kempson, J., Guo, J., Pitts, W.J., Tokarski, J.S., Sack, J.S., Khan, J.A., Lippy, J., Lorenzi, M.V., You, D., McDevitt, T., Vuppugalla, R., Zhang, Y., Lombardo, L.J., Trainor, G.L., Purandare, A.V.

(2015) ACS Med Chem Lett 6: 845-849

  • DOI: https://doi.org/10.1021/acsmedchemlett.5b00225
  • Primary Citation of Related Structures:  
    5CF4, 5CF5, 5CF6

  • PubMed Abstract: 

    Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

    • Organizational Affiliation: 

    Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK2
A, B
321Homo 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
50O
Query on 50O
Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]		N,N-dicyclopropyl-6-[(2S)-2,3-dihydroxypropyl]-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide
C20 H26 N6 O3
FHJUPPRBBPCLDY-ZDUSSCGKSA-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
50O BindingDB:  5CF6 IC50: min: 8.2, max: 720 (nM) from 2 assay(s)
Binding MOAD:  5CF6 IC50: 8.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.214 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.187 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 111.64α = 90
b = 111.64β = 90
c = 70.417γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
HKL-2000data scaling
BUSTERrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2015-08-26 
    • Deposition Author(s): Sack, J.S.

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-26
    Type: Initial release
  • Version 1.1: 2015-09-02
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Derived calculations, Refinement description