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ever, once an NNRTI is bound to RT, only the first putative entrance remains accessible; the second
disappears due to the conformational change and repositioning of the β12-β13-β14 sheet [43].
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It is evident, from comparison of the various HIV-1 RT structures that the NNIBP has a highly flexible
structure that apparently allows the enzyme to accommodate various types of NNRTIs with different
shapes and sizes. Despite apparent differences in the structures of the bound inhibitors, comparison of
structures of several HIV-1 RT/NNRTI complexes revealed remarkable similarity in the geometry of
both the bound inhibitors and the NNIBP [33,35]. All these chemically diverse NNRTIs assume a
strikingly similar butterfly-like shape (Figure 6). The binding of NNRTIs in the NNIBP can be likened
to a butterfly sitting on the β6-β10-β9 sheet and facing toward the putative entrance to the pocket. The
angle between the two wings of the “butterfly” is approximately 112–115° in the TIBO, α-APA, and
nevirapine complexes [35]. This angle might be critical in inhibitor binding and could be a crucial
parameter in the design of new NNRTIs. There are many other NNRTIs that are significantly larger or
smaller in size than α-APA, TIBO, or nevirapine. It is very likely that the NNIBP can adopt other
conformations. For example, BHAP appears to be too large to fit into the NNIBP in any of the reported
HIV-1 RT/NNRTI complexes. The NNIBP in the HIV-1 RT/BHAP complex would need to be
significantly larger than that observed in the structures of the known HIV-1 RT/NNRTI complexes. It is
possible that the BHAP inhibitor may not conform to a butterfly-like shape. This underscores the
importance of solving crystal structures for as many HIV-1 RT/NNRTI complexes as possible.
Additional structural and biochemical data for other HIV-1 RT/NNRTI complexes should provide the
insight needed to define the limits of the flexibility of HIV-1 RT in the NNIBP region.
VII. Process of NNRTI Binding
In crystal structures of unliganded HIV-1 RT [40,41,43] and of HIV-1 RT/DNA/Fab complex [38], the
NNIBP does not exist (although a small cavity is found in the region of the NNIBP proximal to the
polymerase active site in the unliganded HIV-1 RT structure described by Esnouf et al. [42]). In these
structures, the side chains of Tyr181 and Tyr188 in p66 point away from the polymerase active site and
toward the hydrophobic core. However, in the HIV-1 RT/NNRTI complex structures, the side chains of
Tyr181 and Tyr188 point toward the polymerase active site, and the side chain of Tyr181 is in a position
that prevents Trp229 from occupying the position it has in the unliganded or DNA bound HIV-1 RT
structures. Binding an NNRTI also moves the β12-β13-β14 sheet away from the hydrophobic core
[34,35,37]. These conformational
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