Probing the structural and molecular basis of nucleotide selectivity by human mitochondrial DNA polymerase γ

Abstract

Significance Nucleoside analog reverse transcriptase inhibitors (NRTIs) are the cornerstones of treatment for fighting HIV infection. Unfortunately, they also cause drug toxicity by inhibiting human mitochondrial DNA polymerase (Pol γ). Identification of structural differences between the intended target (RT) and adverse reaction target (Pol γ) will provide critical information for designing more potent drugs with lower toxicity. Here, we reveal structural and mechanistic differences between Pol γ and RT by studying NRTIs that have comparable efficacy on RT but significantly different affinities for Pol γ. We identified critical discriminator residues in Pol γ that are fully responsible for its differential response to emtricitabine. More importantly, the topological equivalent residue in RT is essential for activity, thus identifying this region as a hot-spot for inhibitor design.