Structural Basis of HIV‑1 Inhibition by Nucleotide-Competing Reverse Transcriptase Inhibitor INDOPY‑1

HIV-1 reverse transcriptase (RT)
is an essential enzyme, targeting
half of approved anti-AIDS drugs. While nucleoside RT inhibitors (NRTIs)
are DNA chain terminators, the nucleotide-competing RT inhibitor (NcRTI)
INDOPY-1 blocks dNTP binding to RT. Lack of structural information
hindered INDOPY-1 improvement. Here we report the HIV-1 RT/DNA/INDOPY-1
crystal structure, revealing a unique mode of inhibitor binding at
the polymerase active site without involving catalytic metal ions.
The structure may enable new strategies for developing NcRTIs.