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PDBsum entry 1k2p
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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 structure of bruton'S tyrosine kinase domain suggests a novel pathway for activation and provides insights into the molecular basis of X-Linked agammaglobulinemia.
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Authors
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C.Mao,
M.Zhou,
F.M.Uckun.
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Ref.
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J Biol Chem, 2001,
276,
41435-41443.
[DOI no: ]
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PubMed id
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Abstract
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Bruton's tyrosine kinase is intimately involved in signal transduction pathways
regulating survival, activation, proliferation, and differentiation of B lineage
lymphoid cells. Mutations in the human btk gene are the cause of X-linked
agammaglobulinemia, a male immune deficiency disorder characterized by a lack of
mature, immunoglobulin-producing B lymphocytes. We have determined the x-ray
crystal structure of the Bruton's tyrosine kinase kinase domain in its
unphosphorylated state to a 2.1 A resolution. A comparison with the structures
of other tyrosine kinases and a possible mechanism of activation unique to
Bruton's tyrosine kinase are provided.
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Figure 2.
Fig. 2. Panel a, backbone positions of the A loop and
 C helix for
BTK-KD (green), phospho-LCK (red), and c-SRC (white) are
superimposed to illustrate their conformational differences and
similarities. An AMP-PNP molecule ( pink) is present in the
c-SRC crystal structure and was used to mark the location of
active site. The side chains of Arg-544 and Tyr-551 in BTK and
their equivalent residues in LCK and c-SRC on the A loop are
shown. All coordinates were superimposed in CHAIN (28). Prepared
using Insight II. Panel b, the noninhibitory (BTK) and
inhibitory (IRK) conformations of the A loop are illustrated.
Both crystal structures were first superimposed and shown
separately in the same orientation with the A loops highlighted
in rainbow tubes. Neither of the activation tyrosines is
phosphorylated in the crystal structures. Prepared with GRASP
(56).
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Figure 3.
Fig. 3. Unique activation mechanism proposed based on the
crystal structures of BTK-KD and phospho-LCK. Panel A,
comparison of the superimposed BTK-KD (white backbones and
multiple color side chains in stick model) and the phospho-LCK
structures (gold backbones and red stick model side chains). The
black lines indicate hydrogen bonds. Panel B, we propose that
critical changes may occur when Arg-544 solely interacts with
phosphotyrosine 551 upon phosphorylation and Arg-544 releases
Glu-445, which subsequently takes part in ATP binding, which may
be a critical component of catalysis. N-lobe, N-terminal lobe;
C-lobe, C-terminal lobe.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2001,
276,
41435-41443)
copyright 2001.
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