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PDBsum entry 4i5c

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protein ligands Protein-protein interface(s) links
Transferase PDB id
4i5c
Jmol
Contents
Protein chains
281 a.a.
293 a.a.
Ligands
C5I ×2
EDO ×4
Waters ×299
PDB id:
4i5c
Name: Transferase
Title: The jak1 kinase domain in complex with inhibitor
Structure: Tyrosine-protein kinase jak1. Chain: a, b. Fragment: protein kinase 2 domain residues 854-1154. Synonym: janus kinase 1, jak-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: jak1, jak1a, jak1b. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
Resolution:
2.10Å     R-factor:   0.193     R-free:   0.245
Authors: R.Fong,P.J.Lupardus
Key ref: C.A.Hurley et al. (2013). Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1. Bioorg Med Chem Lett, 23, 3592-3598. PubMed id: 23642482 DOI: 10.1016/j.bmcl.2013.04.018
Date:
28-Nov-12     Release date:   22-May-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P23458  (JAK1_HUMAN) -  Tyrosine-protein kinase JAK1
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1154 a.a.
281 a.a.
Protein chain
Pfam   ArchSchema ?
P23458  (JAK1_HUMAN) -  Tyrosine-protein kinase JAK1
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1154 a.a.
293 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.2.7.10.2  - Non-specific protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+ [protein]-L-tyrosine
= ADP
+ [protein]-L-tyrosine phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     4 terms  

 

 
    reference    
 
 
DOI no: 10.1016/j.bmcl.2013.04.018 Bioorg Med Chem Lett 23:3592-3598 (2013)
PubMed id: 23642482  
 
 
Novel triazolo-pyrrolopyridines as inhibitors of Janus kinase 1.
C.A.Hurley, W.S.Blair, R.J.Bull, C.Chang, P.H.Crackett, G.Deshmukh, H.J.Dyke, R.Fong, N.Ghilardi, P.Gibbons, P.R.Hewitt, A.Johnson, T.Johnson, J.R.Kenny, P.B.Kohli, J.J.Kulagowski, M.Liimatta, P.J.Lupardus, R.J.Maxey, R.Mendonca, R.Narukulla, R.Pulk, S.Ubhayakar, A.van Abbema, S.I.Ward, B.Waszkowycz, M.Zak.
 
  ABSTRACT  
 
The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib).