Structure-activity Relationships of Hiv-1 Reverse Transc

Environmental Health Sciences

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Abstract

SUMMARY OF WORK: Through studies of the RT's mechanism, our laboratory, in collaboration with others, discovered that the mutation propensity is linked to how strongly the enzyme stays attached to the DNA template during replication. Thus, if RT falls off the viral template during replication, RT tends to make an error (or mutation) at the point where it climbs back on the template and continues replication. This mechanism appears to account for a portion of the HIV-1 genetic hypervariability. Much insight into the mechanism of "falling off" has been gained by combining structural information on RT with biochemical studies of the wild-type enzyme and enzymes altered in specific amino acid residues that control affinity of binding to the template. Future work emphasizes the role that DNA structure plays in the key polymerase function of selection of the correct nucleotide for insertion into the growing DNA strand. We have studied the roles of amino acids that make contact with the template base and incoming nucleotide, especially R72, and the surrounding amino acids.