Heptad repeat 1 domain of viral class I fusion proteins (HR1 domain)

The Heptad Repeat 1 (HR1) domain is a critical structural component of viral class I fusion proteins, found in a wide range of enveloped viruses including HIV-1, coronaviruses (SARS-CoV-2, MERS-CoV), and influenza (NIH, 2019; MDPI, 2024). It typically resides in the C-terminal fusion subunit, such as gp41 in HIV or S2 in coronaviruses, and is characterized by a repeating pattern of seven amino acids that facilitates the formation of alpha-helical coiled-coils (NIH, 2019; PNAS, 2004). During the fusion process, the HR1 domain assembles into a central trimeric coiled-coil, which then serves as a template for the Heptad Repeat 2 (HR2) domains to fold back and bind into its hydrophobic grooves (NIH, 2019; NIH, 2023). This interaction results in a highly stable six-helix bundle (6HB) structure that pulls the viral and host cell membranes together, enabling membrane fusion and viral entry (NIH, 2019; PNAS, 2004). Therapeutic strategies targeting the HR1 domain primarily involve fusion inhibitors, such as the FDA-approved drug Enfuvirtide, which are often peptides derived from the HR2 sequence that competitively bind to HR1 and prevent 6HB formation (MDPI, 2024; NIH, 2020). Despite their efficacy, these inhibitors often face challenges such as the requirement for subcutaneous injection and the potential for viruses to develop resistance through mutations within the HR1 domain (MDPI, 2024).

Other names

N-terminal heptad repeatN-HRHRAN-heptad repeat regionHeptad repeat 1

Fusion inhibition by binding to the hydrophobic grooves of the HR1 trimer in the pre-hairpin intermediate state, thereby preventing the HR2 domain from packing against HR1 to form the six-helix bundle (6HB) required for membrane fusion.