6NZE

CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH Compound_5 AKA 4-[(2-CARBAMOYLPHEN YL)AMINO]-6-[(5-FLUOROPYRIDIN-2-YL)AMINO]-N-METHYLPYRIDINE -3-CARBOXAMIDE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free: 
    0.227 (Depositor), 0.230 (DCC) 
  • R-Value Work: 
    0.196 (Depositor), 0.200 (DCC) 
  • R-Value Observed: 
    0.197 (Depositor) 

Starting Model: experimental
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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted L8YClick on this verticalbar to view details

This is version 1.3 of the entry. See complete history


Literature

Identification ofN-Methyl Nicotinamide andN-Methyl Pyridazine-3-Carboxamide Pseudokinase Domain Ligands as Highly Selective Allosteric Inhibitors of Tyrosine Kinase 2 (TYK2).

Moslin, R.Zhang, Y.Wrobleski, S.T.Lin, S.Mertzman, M.Spergel, S.Tokarski, J.S.Strnad, J.Gillooly, K.McIntyre, K.W.Zupa-Fernandez, A.Cheng, L.Sun, H.Chaudhry, C.Huang, C.D'Arienzo, C.Heimrich, E.Yang, X.Muckelbauer, J.K.Chang, C.Tredup, J.Mulligan, D.Xie, D.Aranibar, N.Chiney, M.Burke, J.R.Lombardo, L.Carter, P.H.Weinstein, D.S.

(2019) J Med Chem 62: 8953-8972

  • DOI: https://doi.org/10.1021/acs.jmedchem.9b00443
  • Primary Citation of Related Structures:  
    6NZE, 6NZF, 6NZH

  • PubMed Abstract: 

    As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4 , identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit ( 4 ) to potent and selective molecules such as 47 and 48 . The discoveries described herein were critical to the eventual identification of the clinical TYK2 JH2 inhibitor (see following report in this issue). Compound 48 provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Non-receptor tyrosine-protein kinase TYK2
A, B
317Homo sapiensMutation(s): 0 
Gene Names: TYK2
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P29597 (Homo sapiens)
Explore P29597 
Go to UniProtKB:  P29597
PHAROS:  P29597
GTEx:  ENSG00000105397 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29597
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.96 Å
  • R-Value Free:  0.227 (Depositor), 0.230 (DCC) 
  • R-Value Work:  0.196 (Depositor), 0.200 (DCC) 
  • R-Value Observed: 0.197 (Depositor) 
Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 69.59α = 90
b = 65.36β = 112.17
c = 74.54γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing

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 L8YClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-07-24
    Type: Initial release
  • Version 1.1: 2019-11-06
    Changes: Data collection, Database references
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Refinement description
  • Version 1.3: 2024-10-23
    Changes: Structure summary