5W86

CRYSTAL STRUCTURE OF JAK3 KINASE DOMAIN WITH A 4,6-DIAMINONICOTINAMIDE INHIBITOR (COMPOUND NUMBER 7)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.61 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.211 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors.

Bhide, R.S.Keon, A.Weigelt, C.Sack, J.S.Schmidt, R.J.Lin, S.Xiao, H.Y.Spergel, S.H.Kempson, J.Pitts, W.J.Carman, J.Poss, M.A.

(2017) Bioorg Med Chem Lett 27: 4908-4913

  • DOI: https://doi.org/10.1016/j.bmcl.2017.09.029
  • Primary Citation of Related Structures:  
    5W84, 5W85, 5W86

  • PubMed Abstract: 

    The identification of small molecule inhibitors of IRAK4 for the treatment of autoimmune diseases has been an area of intense research. We discovered novel 4,6-diaminonicotinamides which potently inhibit IRAK4. Optimization efforts were aided by X-ray crystal structures of inhibitors bound to IRAK4. Structure activity relationship (SAR) studies led to the identification of compound 29 which exhibited sub-micromolar potency in a LTA stimulated cellular assay.


  • Organizational Affiliation

    Discovery Chemistry, Research & Development, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08543, United States. Electronic address: bhider09@gmail.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK3
A, B, C, D
287Homo sapiensMutation(s): 2 
Gene Names: JAK3
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P52333 (Homo sapiens)
Explore P52333 
Go to UniProtKB:  P52333
PHAROS:  P52333
GTEx:  ENSG00000105639 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP52333
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A, B, C, D
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
9YV BindingDB:  5W86 IC50: 2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.61 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.209 
  • R-Value Observed: 0.211 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.983α = 90
b = 112.297β = 90.06
c = 97.119γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2017-10-11 
  • Deposition Author(s): Sack, J.S.

Revision History  (Full details and data files)

  • Version 1.0: 2017-10-11
    Type: Initial release
  • Version 1.1: 2017-10-25
    Changes: Database references