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Article Dans Une Revue Biochemistry Année : 1999

The Thumb Domain of the P51-Subunit Is Essential for Activation of HIV Reverse Transcriptase

Résumé

The biologically relevant and active form of human immunodeficiency virus reverse transcriptase is a heterodimer produced in a two-step dimerization process. Dimerization involves first the rapid association of the two subunits, followed by a slow conformational change yielding a fully active form. In the present study, we demonstrate that the interaction between the thumb domain of p51 and the RNase-H domain of p66 plays a major role in an essential conformational change required for proper folding of the primer/template and the tRNA-binding site, for maturation and for activation of heterodimeric reverse transcriptase. A synthetic peptide derived from the sequence within the thumb domain of p51, which forms the interface with the RNase-H domains of p66, binds heterodimeric reverse transcriptase with an apparent dissociation constant in the nanomolar range and selectively inhibits activation of heterodimeric reverse transcriptase with an inhibition constant of 1.2 microM. A detailed study of the mechanism of inhibition reveals that this peptide does not require dissociation of heterodimeric RT for efficient inhibition and does not affect subunit association, but interferes with the conformational change required for activation of heterodimeric reverse transcriptase, resulting in a decrease in the affinity of reverse transcriptase for the tRNA and an increase in the stability of the primer/template/reverse transcriptase complex. We have previously proposed that the dimeric nature of reverse transcriptase represents an interesting target for the design of antiviral agents. On the basis of this work, we propose that the conformational changes involved in the activation of reverse transcriptase similarly represent an important target for the design of novel antiviral compounds.

Dates et versions

hal-03130138 , version 1 (03-02-2021)

Identifiants

Citer

May Morris, Cedric Berducou, Jean Mery, Frederic Heitz, Gilles Divita. The Thumb Domain of the P51-Subunit Is Essential for Activation of HIV Reverse Transcriptase. Biochemistry, 1999, 38 (46), pp.15097-15103. ⟨10.1021/bi9914558⟩. ⟨hal-03130138⟩
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