Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA

AZT (3′‐azido‐3′‐deoxythymidine) resistance involves the enhanced excision of AZTMP from the end of the primer strand by HIV‐1 reverse transcriptase. This reaction can occur when an AZTMP‐terminated primer is bound at the n ucleotide‐binding site (pre‐translocation complex N) but not at the ‘ p riming’ site (post‐translocation complex P). We determined the crystal structures of N and P complexes at 3.0 and 3.1 Å resolution. These structures provide insight into the structural basis of AZTMP excision and the mechanism of translocation. Docking of a dNTP in the P complex structure suggests steric crowding in forming a stable ternary complex that should increase the relative amount of the N complex, which is the substrate for excision. Structural differences between complexes N and P suggest that the conserved YMDD loop is involved in translocation, acting as a springboard that helps to propel the primer terminus from the N to the P site after dNMP incorporation.