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Figure 6.
Fig. 6. Sites of mutations conferring resistance to various
nucleoside analog drugs. (A) "Front" view, corresponding to the
orientation in Fig. 4. The polypeptide backbone of the fingers
and palm domains (residues 1 to 235) is shown as a red worm, and
locations of resistance mutations are indicated by colored
squares. The substrates are shown in Corey-Pauling-Koltun
representation, with colors as in Fig. 3. The color code for
mutations is as follows: light blue for resistance to ddI, ddC,
and 3TC; blue for resistance to AZT; and violet for cross
resistance to AZT and ddI or ddC. The location of the NNRTI
binding site is shown by an arrow. Side chains of the residues
at which mutations affect dideoxynucleotide sensitivity project
forward: L74 bears on the templating base, and V at this
position will also shift Q151 and R72 and hence the dNTP itself;
M184 contacts the backbone and base at the primer terminus, and
mutation to I or V will also generate a contact to the sugar
ring of the dNTP; K65 contacts the  -phosphate;
and T69D (resistance to ddC) can probably best be explained by
assuming a conformational effect on the fingers loop,
transmitted to the dNTP by contacts from other fingers residues.
(B) "Back" view, from the direction opposite to the one in (A).
Side chains of AZT resistance mutations project toward this
surface. One of the earliest mutations that appears in patients
on AZT monotherapy is K70R. The Lys70 residue projects directly
outward in the current model, but mutation to arginine (with
five hydrogen-bond donors in fixed orientations on the
guanidinium group) could readily induce side-chain
reorientation, with contacts to Asp113 or the -phosphate.
Subsequent appearance of T215Y/F confers higher levels of
resistance. This mutation, likely to affect the rear of the 3'
pocket, is frequently "tuned" by appearance of others: K210W
(which probably stabilizes the alteration at 215), M41L, and
D67N and K219Q (which likely affect the interaction of fingers
and palm and hence the formation of the 3' pocket during the
polymerization cycle) (16). Figure 4A was prepared with GRASP
(50), and Figs. 3, 4B, 5, and 6, with RIBBONS (51).
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