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PDBsum entry 4ivd

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protein ligands Protein-protein interface(s) links
Transferase/transferase inhibitor PDB id
4ivd
Jmol
Contents
Protein chain
292 a.a.
Ligands
15T ×2
Waters ×327
PDB id:
4ivd
Name: Transferase/transferase inhibitor
Title: Jak1 kinase (jh1 domain) in complex with compound 34
Structure: Tyrosine-protein kinase jak1. Chain: a, b. Fragment: unp 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:
1.93Å     R-factor:   0.204     R-free:   0.247
Authors: C.Eigenbrot,M.Steffek
Key ref: M.Zak et al. (2013). Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2. J Med Chem, 56, 4764-4785. PubMed id: 23659214 DOI: 10.1021/jm4004895
Date:
22-Jan-13     Release date:   22-May-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P23458  (JAK1_HUMAN) -  Tyrosine-protein kinase JAK1
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1154 a.a.
292 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: 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: 10.1021/jm4004895 J Med Chem 56:4764-4785 (2013)
PubMed id: 23659214  
 
 
Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2.
M.Zak, C.A.Hurley, S.I.Ward, P.Bergeron, K.Barrett, M.Balazs, W.S.Blair, R.Bull, P.Chakravarty, C.Chang, P.Crackett, G.Deshmukh, J.DeVoss, P.S.Dragovich, C.Eigenbrot, C.Ellwood, S.Gaines, N.Ghilardi, P.Gibbons, S.Gradl, P.Gribling, C.Hamman, E.Harstad, P.Hewitt, A.Johnson, T.Johnson, J.R.Kenny, M.F.Koehler, P.Bir Kohli, S.Labadie, W.P.Lee, J.Liao, M.Liimatta, R.Mendonca, R.Narukulla, R.Pulk, A.Reeve, S.Savage, S.Shia, M.Steffek, S.Ubhayakar, A.van Abbema, I.Aliagas, B.Avitabile-Woo, Y.Xiao, J.Yang, J.J.Kulagowski.
 
  ABSTRACT  
 
Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.