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Figure
Continued
consequence, the p51 submit has no cleft for binding nucleic acid substrates and hence no polymerase
activity.
Page 48
There is considerable evidence showing that HIV-1 RT is quite flexible and that this flexibility is
essential for DNA polymerization. Comparisons among DNA-bound, inhibitor-bound, and unliganded
HIV-1 RT structures provide a demonstration of the enzyme's flexibility. When a DNA template-primer
binds to HIV-1 RT, structural elements of the fingers, palm, and thumb subdomains of the p66 subunit
form a clamp-like structure that holds the nucleic acid (Figure 2) [38]. The template-primer substrate
interacts with amino acid residues of the fingers, palm, and thumb subdomains, especially in the regions
denoted as “primer grip” and “template grip,” believed to position the template-primer precisely relative
to the polymerase active site [38]. The primary contacts between the template-primer and the protein are
along the sugar-phosphate backbone of the DNA and thus are not sequence-specific [38]. In the absence
of nucleic acid template-primer or NNRTI, the thumb subdomain of p66 is folded down into the DNAbinding
cleft and lies near the fingers subdomain (Figure 2) [40,41,43]. As a consequence, the DNAbinding
cleft is closed. However, even in the absence of a bound nucleic acid, binding of an NNRTI
induces both short-range and long-range structure distortions, including a hinge-like movement near the
base of the p66 thumb that constrains the p66 thumb in a conformation that is extended beyond the
upright
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