Structure of ancient viral protein offers new therapeutic possibilities in areas of cancer and autoimmunity

Nikos Nikolopoulos and Professor Yorgo Modis from the University of Cambridge Department of Medicine Molecular Immunity Unit have determined the atomic structure of the human endogenous retrovirus K (HERV-K) envelope glycoprotein (Env), revealing structural features that could inform future therapeutic strategies.

Approximately 15% of our genome consists of HERVs and other remnants of ancient viral infections, which can be inherited through generations. 

While most of these sequences are inactive, the HERV-K family remains remarkably intact. Expression of the HERV-K Env has been closely associated with the progression of various cancers, neurodegeneration, and autoimmune diseases.

The study, published today in the Journal of Virology, provides an atomic-level map of the HERV-K Env surface subunit.

The team at Cambridge determined the three-dimensional architecture of the HERV-K Env surface subunit at 2.25 Å resolution.

The structure reveals 5 disulfide bonds that contribute to the protein’s stability and function. Two extended loops on the surface were identified as potential sites where the virus interacts with human cells.

Although HERV-K Env shares some similarities with other retroviral envelope proteins, it adopts a markedly distinct structural arrangement compared with well-characterised glycoproteins such as those of HIV-1, suggesting differences in how it functions and interacts with host cells.

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We were excited to identify potential binding sites for drug-like molecules and carbohydrates in our structure of HERV-K Env. These are the most likely sites to trigger autoimmune responses. Thanks to our structure we now have an atomic-resolution map that will help guide the development of new therapies targeting HERV-K Env.

Professor Yorgo Modis, study lead and Professor of Virology and Immunology from the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID)

Further, the team also identified hydrophobic "pockets" on the surface of the protein that could potentially accommodate small, drug-like molecules, providing starting points for future structure-guided therapeutic development.

Together, these findings provide a vital platform to understand how retroviruses function in humans, which lay the groundwork for future studies exploring its role in disease and its potential as a therapeutic target.

This research was supported by the Wellcome Trust.