Inhibitor binding alters the
directions of motions in HIV-1 reverse transcriptase
CONCLUSIONS
Nevirapine
binding imparts a significant change in the orientation of global motions,
while the sizes of motions are marginally affected (Figure 1).
Efavirenz,
the second generation NNRTI known to inhibit RT more effectively, has the
additional effect of effectively suppressing the amplitude of motion at the
p66 thumb, in addition to affecting the orientations of domain movements.
Two
mechanisms thus appear to underlie drug inhibition: (i) changing the
directions of domain fluctuations, (ii) obstructing them all together.
The
efficiency of these inhibitors originates from their interference with the
global hinge-bending site at the connection of the p66 fingers and thumb
with the palm subdomain of p66.
Our
detailed analysis of the molecular mechanisms of domain movements reveals
another hinge site controlling the movements of the RNase H domain.
University of Pittsburgh ---------- School of Medicine
W1041 Biomedical Science Tower 200 Lothrop St., Pittsburgh, PA
15261. Phone : (412) 648-3333, Fax: (412) 648-3163
