THE STRUCTURE OF HIV-1 REVERSE-TRANSCRIPTASE COMPLEXED WITH AN RNA PSEUDOKNOT INHIBITOR

Small RNA pseudoknots, selected to bind human immunodeficiency virus t ype 1 (HIV-1) reverse transcriptase tightly, are potent inhibitors of reverse transcriptase, The co-crystal structure of reverse transcripta se complexed with a 33 nucleotide RNA pseudoknot has been determined b y fitting the ligand into a high quality, 4-fold averaged 4.8 Angstrom resolution electron density map. The RNA is kinked between stems S1 a nd S2, thereby optimizing its contacts with subunits of the heterodime r, Its binding site extends along the cleft that lies between the poly merase and RNase H active sites, partially overlaps with that observed for duplex DNA and presumably overlaps some portion of the tRNA site. Stem S2 and loop L1 stabilize the 'closed' conformation of the polyme rase through extensive electrostatic interactions with several basic r esidues in helix I of the p66 thumb and in the p66 fingers domain. Pre sumably, this RNA ligand inhibits reverse transcriptase by binding to a site that partly overlaps the primer-template binding site.