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Figure 4.
Three distinct mechanisms of NRTI resistance through
mutations at three distinct sites. Superposition of
excision-enhancing mutation or TAM (M41L, D67N, K70R, T215Y, and
K219Q) RT·dsDNA·AZTppppA structure^4 on K65R
RT·dsDNA·dATP structure at their dNTP-binding
sites; AZTppppA is the product of AZT monophosphate by
ATP-mediated excision. Although the two structures contained two
distinct sites of mutations and crystallized in two distinct
space groups, they superimpose very well at the active site
region. The mutated residues Arg^70 and Tyr^215 are from the
crystal structure of excision-enhancing mutation RT complex,
whereas M184V was modeled based on the structure of the M184V
RT·dsDNA binary complex (49). The surfaces of the
K65R/Arg^72 platform (gray mesh) and M184V (3TC resistance
mutation site; magenta mesh) form two walls on either side of
the ribose ring, whereas the other end of the K65R/Arg^72
platform interfaces with K70R, a primary mutation site for AZT
resistance.
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