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Figure 9.
FIGURE 9. Inhibition by extra-catalytic domains in c-Src
and MARK. Catalytic domains are in blue with activation segments
(ASeg) in yellow; hinge regions are marked by white circles. All
molecules are shown in the same orientation as determined by
least squares fitting of helices E and F of the C-lobes. a,
restrained (inactive) conformation of human c-Src (PDB code 2SRC
(38)). The SH3 and SH2 domains of c-Src are N-terminal to the
catalytic domain. The SH3 domain and the linker between SH2 and
catalytic domain bind together to the N-lobe and are shown in
the same color (red). The SH2 domain binds to the tail of the
catalytic domain via interaction with phosphotyrosine Tyr-527.
The connector between the SH3 and the SH2 domain (lock, shown in
green) is essential for inhibition of c-Src as it efficiently
restricts breathing movements of the catalytic domain (36). b,
MARK, represented by molecule E of the MARK1 crystal structure.
c, hypothetical active conformation of MARK, with activation
segment and orientation of the N-lobe (and UBA domain) relative
to the C-lobe modeled by comparison with Aurora A, active
conformation (PDB code 1OL5 (41)). Rotation of the UBA domain in
synchrony with the N-lobe is accomplished by unfolding the base
of the linker (labeled CD in analogy to CD domains of MAP
kinases (42)). According to this model, efficient damping of the
catalytic domain breathing movements requires stabilization of
the CD domain by binding of another interaction partner.
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