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Figure 5.
Celecoxib binding to ovCOX-1 as determined by x-ray
crystallography. (A) A stereoview of celecoxib (yellow) in the
active site of COX-1 in the celecoxib/ovCOX-1 structure shown
with omit F[o]-F[c] difference density contoured at 2.8σ
(gray). Residues in the active site are displayed in green,
whereas celecoxib is in yellow. Residues Arg120, Tyr355, and
Glu524 lie at the mouth of the COX active site, whereas the
catalytic Tyr385 hydrogen bonded to Tyr348 are located at the
apex of the hydrophobic channel. (B) Stereoview of
celecoxib/ovCOX-1 structure with the opening from the membrane
binding domain into the COX active site oriented along plane of
the page. Comparison of celecoxib/ovCOX-1 complex (green) and
the reference model (1Q4G) (superimposed yellow ribbon and
yellow side chains) shows that Ile523, homologous to Val523 in
COX-2, adopts an extended rotamer conformation allowing access
to the otherwise inaccessible hydrophobic side pocket comprised
of residues Leu352, Ser353, Ile517, and Phe518 (some side chains
are omitted for clarity). The residues His513 and Gln192
contribute to the outer shell of the side pocket and are
included in the figure. Rendering of celecoxib atoms as spheres
highlight the steric clash of Ile523 (yellow sticks in bottom
panel) with the reference model. In Fig. S6 the positions of the
α-carbons of residues 510–520 in the celecoxib/ovCOX-1 and
the AA/ovCOX-1 (1DIY) structures relative to the reference model
(1Q4G) are compared. (C) Stereoview of two alternate
conformations of residues 121–129 in monomer B at the dimer
interface traced into the electron density. Monomer A (orange)
is shown with celecoxib bound (yellow) and monomer B is shown in
the two conformations representing the conformation in the
absence of bound inhibitor (blue) and the shift induced by
binding of celecoxib (magenta). The side chains of Ser126 and
Pro127 are shown in the two conformations and represented as
inhibitor bound (+) and unbound (-) next to Glu543 (E543) of the
partner monomer also in an alternate conformation. The position
of celecoxib in monomer A (yellow sticks) and active site
residues Arg120, Glu524, Tyr355, Ser530, and Tyr385 are shown
for spatial orientation. Celecoxib in monomer B, which was
refined to 50% occupancy in the final model, has been removed to
represent the unbound monomer. (D) Enlarged view of the boxed
area at the dimer interface shown in C.
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