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Figure 3
Overall structure of HIV-1 RT p66/p51 heterodimer [38] showing the locations
of the major target sites for anti-HIV-1 RT inhibitors. The NRTIs target the dNTP-binding
site/the polymerase active site (shown as a small striped circle) that lies at the
floor of the DNA-binding cleft. The NNRTIs bind to the NNIBP (shown as a large
dotted circle), which is near, but distinct from, the polymerase active site. The RNase H
domain is located at the C-terminal of the p66 subunit. The RNase H catalytic site
(shown as a medium circle) is an attractive target site for anti-HIV-1 drugs. The HIV-1
RT p66/p51 heterodimer interface is shown as a dashed line. Since HIV-1 RT functions
as a heterodimer, any inhibitors that could interfere with the dimerization process might
also be potential drugs for treating HIV-1 infection.
position of the thumb observed in the HIV-1 RT/DNA/Fab structure [31,33–37,43].
In the unliganded structure of HIV-1 RT reported by Esnouf et al. [42], the p66 thumb subdomain is in
an upright conformation different from that observed in the other unliganded HIV-1 RT structures but
similar to that found in the DNA-bound HIV-1 RT and NNRTI-bound HIV-1 RT structures. Esnouf et
al. [42] contend that the upright conformation of the p66 thumb subdomain in their unliganded RT
structure is appropriate for unliganded HIV-1 RT and that the binding of an NNRTI does not affect the
conformation of the p66 thumb. However, we believe that the conformation of the p66 thumb in the
Esnouf et al. structure may well be a result of the method used to prepare the
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