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PDBsum entry 3eyh
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protein ligands links
Transferase PDB id
3eyh

 

 

 

 

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Contents
Protein chain
287 a.a. *
Ligands
IZA
Waters ×223
* Residue conservation analysis
PDB id:
3eyh
Name: Transferase
Title: Crystal structures of jak1 and jak2 inhibitor complexes
Structure: Tyrosine-protein kinase. Chain: a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: jak1, hcg_22179. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.00Å     R-factor:   0.178     R-free:   0.237
Authors: N.K.Williams,R.S.Bamert,O.Patell,C.Wang,P.M.Walden,E.Fantino
Key ref:
N.K.Williams et al. (2009). Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J Mol Biol, 387, 219-232. PubMed id: 19361440 DOI: 10.1016/j.jmb.2009.01.041
Date:
20-Oct-08     Release date:   03-Feb-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P23458  (JAK1_HUMAN) -  Tyrosine-protein kinase JAK1 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1154 a.a.
287 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.2.7.10.2  - non-specific protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
L-tyrosyl-[protein]
 + ATP
 = O-phospho-L-tyrosyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
DOI no: 10.1016/j.jmb.2009.01.041 J Mol Biol 387:219-232 (2009)
PubMed id: 19361440  
 
 
Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains.
N.K.Williams, R.S.Bamert, O.Patel, C.Wang, P.M.Walden, A.F.Wilks, E.Fantino, J.Rossjohn, I.S.Lucet.
 
  ABSTRACT  
 
The Janus kinases (JAKs) are a pivotal family of protein tyrosine kinases (PTKs) that play prominent roles in numerous cytokine signaling pathways, with aberrant JAK activity associated with a variety of hematopoietic malignancies, cardiovascular diseases and immune-related disorders. Whereas the structures of the JAK2 and JAK3 PTK domains have been determined, the structure of the JAK1 PTK domain is unknown. Here, we report the high-resolution crystal structures of the "active form" of the JAK1 PTK domain in complex with two JAK inhibitors, a tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one (CMP6) and (3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile (CP-690,550), and compare them with the corresponding JAK2 PTK inhibitor complexes. Both inhibitors bound in a similar manner to JAK1, namely buried deep within a constricted ATP-binding site, thereby providing a basis for the potent inhibition of JAK1. As expected, the mode of inhibitor binding in JAK1 was very similar to that observed in JAK2, highlighting the challenges in developing JAK-specific inhibitors that target the ATP-binding site. Nevertheless, differences surrounding the JAK1 and JAK2 ATP-binding sites were apparent, thereby providing a platform for the rational design of JAK2- and JAK1-specific inhibitors.
 
  Selected figure(s)  
 
Figure 4.
Fig. 4. Modes of inhibitor binding to the JAK1 and JAK2 kinase domains. (a) Interaction between CMP6 and JAK1 PTK. (b) Interaction between CP-690,550 and JAK1 PTK. (c) Interaction between CP-690,550 and JAK2 PTK. The left panel shows the side chains of residues that interact with the inhibitor as well as the main-chain atoms and water molecules participating in hydrogen bonds. The right panel shows a corresponding view of the inhibitor in a ball-and-stick representation and covered with the simulated annealing F[o] − F[c] electron density omit map contoured at 3σ. (d) Chemical structures of CMP6 (left) and CP-690,550 (right). Functional group names are indicated, and atoms are labeled according to the Protein Data Bank structure files. Carbon, nitrogen, oxygen and fluorene atoms are shown in yellow, blue, red and gray, respectively. 		Figure 6.
Fig. 6. Comparison of the active-site regions of JAK1 and JAK2. Superposition of JAK1 PTK (green) and JAK2 PTK (cyan) in complex with CMP6 (a) and CP-690,550 (b). Unique residues within 5 Å of the inhibitor are shown.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2009, 387, 219-232) copyright 2009.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22820988 R.M.Bandaranayake, D.Ungureanu, Y.Shan, D.E.Shaw, O.Silvennoinen, and S.R.Hubbard (2012).
Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F.
  Nat Struct Mol Biol, 19, 754-759.
PDB codes: 4fvp 4fvq 4fvr
21283107 A.Quintás-Cardama, H.Kantarjian, J.Cortes, and S.Verstovsek (2011).
Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond.
  Nat Rev Drug Discov, 10, 127-140.  
21439476 C.Haan, C.Rolvering, F.Raulf, M.Kapp, P.Drückes, G.Thoma, I.Behrmann, and H.G.Zerwes (2011).
Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine receptors.
  Chem Biol, 18, 314-323.  
21220115 P.J.Lupardus, G.Skiniotis, A.J.Rice, C.Thomas, S.Fischer, T.Walz, and K.C.Garcia (2011).
Structural snapshots of full-length Jak1, a transmembrane gp130/IL-6/IL-6Rα cytokine receptor complex, and the receptor-Jak1 holocomplex.
  Structure, 19, 45-55.  
21117080 V.Tsui, P.Gibbons, M.Ultsch, K.Mortara, C.Chang, W.Blair, R.Pulk, M.Stanley, M.Starovasnik, D.Williams, M.Lamers, P.Leonard, S.Magnuson, J.Liang, and C.Eigenbrot (2011).
A new regulatory switch in a JAK protein kinase.
  Proteins, 79, 393-401.
PDB codes: 3nyx 3nz0
20868368 G.M.Gordon, Q.T.Lambert, K.G.Daniel, and G.W.Reuther (2010).
Transforming JAK1 mutations exhibit differential signalling, FERM domain requirements and growth responses to interferon-γ.
  Biochem J, 432, 255-265.  
  20072651 J.Li, M.Favata, J.A.Kelley, E.Caulder, B.Thomas, X.Wen, R.B.Sparks, A.Arvanitis, J.D.Rogers, A.P.Combs, K.Vaddi, K.A.Solomon, P.A.Scherle, R.Newton, and J.S.Fridman (2010).
INCB16562, a JAK1/2 selective inhibitor, is efficacious against multiple myeloma cells and reverses the protective effects of cytokine and stromal cell support.
  Neoplasia, 12, 28-38.  
20506481 T.H.Lin, M.Hegen, E.Quadros, C.L.Nickerson-Nutter, K.C.Appell, A.G.Cole, Y.Shao, S.Tam, M.Ohlmeyer, B.Wang, D.G.Goodwin, E.F.Kimble, J.Quintero, M.Gao, P.Symanowicz, C.Wrocklage, J.Lussier, S.H.Schelling, A.G.Hewet, D.Xuan, R.Krykbaev, J.Togias, X.Xu, R.Harrison, T.Mansour, M.Collins, J.D.Clark, M.L.Webb, and K.J.Seidl (2010).
Selective functional inhibition of JAK-3 is sufficient for efficacy in collagen-induced arthritis in mice.
  Arthritis Rheum, 62, 2283-2293.  
20191331 Y.Hitoshi, N.Lin, D.G.Payan, and V.Markovtsov (2010).
The current status and the future of JAK2 inhibitors for the treatment of myeloproliferative diseases.
  Int J Hematol, 91, 189-200.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.

 

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