期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：27
DOI：10.1073/pnas.2200260119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
A large percentage of the human genome is composed of repetitive elements that are relics of past viral infections. Expression of these human endogenous retroviruses (HERVs) is associated with a variety of diseases, including cancer; however, causality remains to be established. A subset of these HERVs express proteins with reverse transcriptase (RT) activity. This has inspired several clinical studies of antiviral RT inhibitors for indications in which HERV expression is associated with disease. We have determined the X-ray structure of an HERV reverse transcriptase. This structure clarifies the reasons for poor inhibition by 3TC (lamivudine) and lack of inhibition by nonnucleoside inhibitors nevirapine and efavirenz. This structure will enable the design of selective HERV-K RT tools for drug target validation.
Human endogenous retroviruses (HERVs) comprise nearly 8% of the human genome and are derived from ancient integrations of retroviruses into the germline. The biology of HERVs is poorly defined, but there is accumulating evidence supporting pathological roles in diverse diseases, such as cancer, autoimmune, and neurodegenerative diseases. Functional proteins are produced by HERV-encoded genes, including reverse transcriptases (RTs), which could be a contributor to the pathology attributed to aberrant HERV-K expression. To facilitate the discovery and development of HERV-K RT potent and selective inhibitors, we expressed active HERV-K RT and determined the crystal structure of a ternary complex of this enzyme with a double-stranded DNA substrate. We demonstrate a range of RT inhibition with antiretroviral nucleotide analogs, while classic nonnucleoside analogs do not inhibit HERV-K RT. Detailed comparisons of HERV-K RT with other known RTs demonstrate similarities to diverse RT families and a striking similarity to the HIV-1 RT asymmetric heterodimer. Our analysis further reveals opportunities for selective HERV-K RT inhibition.
