Inhibitor binding alters the directions of domain motions in HIV-1 reverse transcriptase

 INTRODUCTION

• HIV-1 reverse transcriptase (RT) is a major target for anti-AIDS therapy.

• Two groups of inhibitors have been extensively studied: Non-nucleoside RT inhibitors (NNRTI) and nucleoside analog inhibitors.

 RT STRUCTURE

• RT is a heterodimer.

•  The large 66kDa subunit (p66) contains two domains, DNA polymerase (pol) and RNase H, pol domain in turn is composed of four domains: p66 fingers, p66 thumb, p66 palm and p66 connection. The active site lies on the p66 palm domain between p66 fingers and thumb.

• The smaller 51 kDa subunit (p51) is composed of same subdomains fingers, thumb, connection and palm. But the overall 3-dimensional fold of p51 is different from p66 pol domain.

 ACTIVE SITE AND NNRTI BINDING POCKET

• Three aspartates of the p66 palm subdomain, Asp 110,185,186 form the catalytic triad of RT.

• NNRTI binding pocket is located in a large cleft in p66 palm.

 MODEL

• We used an analytical approach based on a model originating from statistical mechanics of elastic networks. The earlier version of this model is known as Gaussian network model (GNM). GNM was applied successfully to HIV RT 

• GNM has recently been extended to predict the directionalities of collective motions. This new version, called anisotropic network model (ANM), will be used for comparing dynamics of liganded and unliganded RT.

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