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PDBsum entry 1sm2
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structures of interleukin-2 tyrosine kinase and their implications for the design of selective inhibitors.
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Authors
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K.Brown,
J.M.Long,
S.C.Vial,
N.Dedi,
N.J.Dunster,
S.B.Renwick,
A.J.Tanner,
J.D.Frantz,
M.A.Fleming,
G.M.Cheetham.
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Ref.
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J Biol Chem, 2004,
279,
18727-18732.
[DOI no: ]
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PubMed id
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Abstract
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Interleukin-2 tyrosine kinase, Itk, is an important member of the Tec family of
non-receptor tyrosine kinases that play a central role in signaling through
antigen receptors such as the T-cell receptor, B-cell receptor, and Fcepsilon.
Selective inhibition of Itk may be an important way of modulating many diseases
involving heightened or inappropriate activation of the immune system. In
addition to an unliganded nonphophorylated Itk catalytic kinase domain, we
determined the crystal structures of the phosphorylated and nonphosphorylated
kinase domain bound to staurosporine, a potent broad-spectrum kinase inhibitor.
These structures are useful for the design of novel, highly potent and selective
Itk inhibitors and provide insight into the influence of inhibitor binding and
phosphorylation on the conformation of Itk.
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Figure 2.
FIG. 2. Interactions between phosphorylated Itk (pTyr512)
and staurosporine in the ATP-binding site. F[o] - F[c]
experimental electron density for the inhibitor is shown in
cyan, contoured at 1.5  and 2.3 Å
resolution.
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Figure 3.
FIG. 3. Conformational differences in the ATP-binding site
of Btk (cyan ribbons and cyan side chains) and Itk (green
ribbons and green side chains). Unphosphorylated and
phosphorylated Itk adopts a closed catalytic conformation of the
 C-helix and
glycine-rich loop. In contrast, the glycine-rich loop of
unphosphorylated Btk blocks the ATP-binding site, which is not
consistent with inhibitor binding. The Itk gatekeeper residue,
Phe^435, and catalytically important residues are shown in
detail. Itk residue numbering is used unless specified.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2004,
279,
18727-18732)
copyright 2004.
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