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PDBsum entry 3eyh
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References listed in PDB file
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Key reference
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Title
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Dissecting specificity in the janus kinases: the structures of jak-Specific inhibitors complexed to the jak1 and jak2 protein tyrosine kinase domains.
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Authors
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N.K.Williams,
R.S.Bamert,
O.Patel,
C.Wang,
P.M.Walden,
A.F.Wilks,
E.Fantino,
J.Rossjohn,
I.S.Lucet.
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Ref.
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J Mol Biol, 2009,
387,
219-232.
[DOI no: ]
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PubMed id
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Abstract
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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.
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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.
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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.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2009,
387,
219-232)
copyright 2009.
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