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Figure 6.
Fig. 6. (a and b) Alternate sugar pucker of
substrate/inhibitor induced by the plasmodial ADA
Asp172:mammalian ADA Met155 sequence difference. Plasmodial ADA
is cyan and its bound DCF in orange, while mammalian ADA is
green and its bound DCF in pink. Plasmodial ADA Asp172
hydrogen-bonds with the ribose 3′-hydroxyl group, an
interaction that mammalian Met155 is incapable of making. This
causes the plasmodial ADA-bound inhibitor to adopt a C2′-endo
sugar pucker, while the mammalian ADA-bound inhibitor adopts a
C4′-exo pucker. The result is that the 5′-carbon of the two
riboses are oriented significantly differently with respect to
the ribose ring, although the 5′-hydroxyl groups occupy nearly
the same location and are less than 0.4 Å apart. The
different orientations of the 5′-carbon, however, has a great
affect on the space that additions at this position may occupy,
while maintaining a biologically relevant glycosidic linkage
with the purine ring. (c) Stereo view of 5′-PhS-DCF (purple
sticks) docked into the active-site cavity of plasmodial ADA and
superimposed on the crystallographically observed DCF (orange
sticks). The plasmodial ADA crystal structure is cyan, while the
protein following docking is green. The most significant change
in the structure of plasmodial ADA in order to accommodate the
5′-thiophenyl addition is an alternate rotamer adopted by
Phe132, which both enlarges the cavity and stabilizes the 5′
addition.
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