Small-angle X-ray scattering-derived structure of the HIV-1 5' UTR reveals 3D tRNA mimicry

The most conserved region of the HIV type 1 (HIV-1) genome, the ∼335-nt 5' UTR, is characterized by functional stem loop domains responsible for regulating the viral life cycle. Despite the indispensable nature of this region of the genome in HIV-1 replication, 3D structures of multihairpin domains of the 5' UTR remain unknown. Using small-angle X-ray scattering and molecular dynamics simulations, we generated structural models of the transactivation (TAR)/polyadenylation (polyA), primer-binding site (PBS), and Psi-packaging domains. TAR and polyA form extended, coaxially stacked hairpins, consistent with their high stability and contribution to the pausing of reverse transcription. The Psi domain is extended, with each stem loop exposed for interactions with binding partners. The PBS domain adopts a bent conformation resembling the shape of a tRNA in apo and primer-annealed states. These results provide a structural basis for understanding several key molecular mechanisms underlying HIV-1 replication.