Human endogenous retrovirus-K (HERV-K) reverse transcriptase (RT) structure and biochemistry reveals remarkable similarities to HIV-1 RT and opportunities for HERV-K–specific inhibition

• DOI: 10.1073/pnas.2200260119
• Publication Date: 2022-06-30T17:58:11Z
• Authors: Eric T. Baldwin; Matthias Götte; Egor P. Tchesnokov; Eddy Arnold; Margit Hagel; Charles Nichols; Pam Dossang; Marieke Lamers; Paul Wan; Stefan Steinbacher; Donna L. Romero
• Keywords: Endogenous retrovirus

Human endogenous retroviruses (HERVs) comprise nearly 8% of the human genome and are derived from ancient integrations into germline. The biology HERVs is poorly defined, but there accumulating evidence supporting pathological roles in diverse diseases, such as cancer, autoimmune, neurodegenerative diseases. Functional proteins produced by HERV-encoded genes, including reverse transcriptases (RTs), which could be a contributor to pathology attributed aberrant HERV-K expression. To facilitate discovery development RT potent selective inhibitors, we expressed active determined crystal structure ternary complex this enzyme with double-stranded DNA substrate. We demonstrate range inhibition antiretroviral nucleotide analogs, while classic nonnucleoside analogs do not inhibit RT. Detailed comparisons other known RTs similarities families striking similarity HIV-1 asymmetric heterodimer. Our analysis further reveals opportunities for inhibition.