5W85 | pdb_00005w85

CRYSTAL STRUCTURE OF IRAK-4 WITH A 4,6-DIAMINONICOTINAMIDE INHIBITOR (COMPOUND NUMBER 9)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 
    0.251 (Depositor), 0.230 (DCC) 
  • R-Value Work: 
    0.227 (Depositor), 0.220 (DCC) 
  • R-Value Observed: 
    0.227 (Depositor) 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

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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
Interleukin-1 receptor-associated kinase 4
A, B
305Homo sapiensMutation(s): 0 
Gene Names: IRAK4
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NWZ3 (Homo sapiens)
Explore Q9NWZ3 
Go to UniProtKB:  Q9NWZ3
PHAROS:  Q9NWZ3
GTEx:  ENSG00000198001 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9NWZ3
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9YS
Query on 9YS
Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]		6-[(1,3-benzothiazol-6-yl)amino]-4-{[(2S)-1-hydroxy-3-phenylpropan-2-yl]amino}-N-methylpyridine-3-carboxamide
C23 H23 N5 O2 S
MPNICXIXNBEDOD-KRWDZBQOSA-N
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
SEP
Query on SEP
A, B
L-PEPTIDE LINKINGC3 H8 N O6 PSER
TPO
Query on TPO
A, B
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
9YS BindingDB:  5W85 IC50: min: 10, max: 2900 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free:  0.251 (Depositor), 0.230 (DCC) 
  • R-Value Work:  0.227 (Depositor), 0.220 (DCC) 
  • R-Value Observed: 0.227 (Depositor) 
Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 88.44α = 90
b = 125.56β = 90
c = 141.33γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
HKL-2000data scaling
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 9YSClick on this verticalbar to view details

View more in-depth experimental data
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
  • Version 1.2: 2024-11-13
    Changes: Data collection, Database references, Structure summary