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PDBsum entry 2ozo
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References listed in PDB file
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Key reference
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Title
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Structural basis for the inhibition of tyrosine kinase activity of zap-70.
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Authors
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S.Deindl,
T.A.Kadlecek,
T.Brdicka,
X.Cao,
A.Weiss,
J.Kuriyan.
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Ref.
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Cell, 2007,
129,
735-746.
[DOI no: ]
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PubMed id
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Abstract
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ZAP-70, a cytoplasmic tyrosine kinase required for T cell antigen receptor
signaling, is controlled by a regulatory segment that includes a tandem SH2 unit
responsible for binding to immunoreceptor tyrosine-based activation motifs
(ITAMs). The crystal structure of autoinhibited ZAP-70 reveals that the inactive
kinase domain adopts a conformation similar to that of cyclin-dependent kinases
and Src kinases. The autoinhibitory mechanism of ZAP-70 is, however, distinct
and involves interactions between the regulatory segment and the hinge region of
the kinase domain that reduce its flexibility. Two tyrosine residues in the
SH2-kinase linker that activate ZAP-70 when phosphorylated are involved in
aromatic-aromatic interactions that connect the linker to the kinase domain.
These interactions are inconsistent with ITAM binding, suggesting that
destabilization of this autoinhibited ZAP-70 conformation is the first step in
kinase activation.
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Figure 5.
Figure 5. Mutagenesis Identifies Hot Spot Residues in the
Linker-Kinase Sandwich
(A) Two schematic views of ZAP-70,
rotated by 180° with respect to each other, depict the
location of residues in ZAP-70 that are most critical for
autoinhibition. These hot spot residues are indicated by yellow
stars.
(B) LAT phosphorylation by ZAP-70 mutants. The
Tyr315Ala/Tyr319Ala double mutant is referred to as “YYAA.”
Strongly activating alanine mutations at hot spots of the
linker-kinase sandwich are highlighted with yellow stars.
Control experiments in the presence of Lck are shown in Figure
S4.
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Figure 6.
Figure 6. Interaction between the Inter-SH2 Linker and the
Kinase Domain
Detailed view showing the docking of Pro147
in the inter-SH2 linker into the cleft formed by the side chains
of Tyr597 and Tyr598. Helix αI is shown as a light brown
surface, and Tyr597 and Tyr598 are shown in magenta surface
representation.
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The above figures are
reprinted
by permission from Cell Press:
Cell
(2007,
129,
735-746)
copyright 2007.
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