Correlating Conformational
Shift Induction with Altered
Inhibitor Potency in a Multidrug Resistant HIV‑1 Protease Variant
- Publication date
- Publisher
Abstract
Inhibitor-induced conformational ensemble shifts in a
multidrug
resistant HIV-1 protease variant, MDR769, are characterized by site-directed
spin labeling double electron–electron resonance spectroscopy.
For MDR769 compared to the native enzyme, changes in inhibitor IC<sub>50</sub> values are related to a parameter defined as |Δ<i>C</i>|, which is the relative change in the inhibitor-induced
shift to the closed state. Specifically, a linear correlation is found
between |Δ<i>C</i>| and the magnitude of the change
in IC<sub>50</sub>, provided that inhibitor binding is not too weak.
Moreover, inhibitors that exhibit MDR769 resistance no longer induce
a strong shift to a closed conformational ensemble as seen previously
in the native enzyme