Subnanometer structure of an enveloped virus fusion complex on viral surface reveals new entry mechanisms

Area of Science:

• Virology
• Structural Biology
• Molecular Biology

Background:

• Paramyxoviruses, including measles and Nipah viruses, cause significant human and animal diseases.
• Viral entry into host cells is a critical step in infection, mediated by viral glycoproteins.
• The hemagglutinin-neuraminidase (HN) and fusion (F) proteins form a complex essential for paramyxovirus cell entry.

Purpose of the Study:

• To visualize the structure of the human parainfluenza virus 3 (HPIV3) HN/F fusion complex at subnanometer resolution.
• To elucidate the mechanism of viral fusion complex activation and cell entry.
• To identify potential druggable targets for paramyxovirus infections.

Main Methods:

• Cryo-electron tomography (cryo-ET) was employed to image the HN/F complex on authentic clinical virus particles.
• High-resolution structural analysis was performed to determine the spatial arrangement and interactions within the fusion complex.

Main Results:

• The study provides a near-atomic resolution structure of the HPIV3 HN/F complex in situ.
• A specific loop on the HN protein was observed to insert into a pocket on the F protein, maintaining the complex in a quiescent state.
• Distinct conformations of the HN heads were visualized, with one interacting with F and the other poised to bind cellular receptors, detailing sequential steps before fusion.

Conclusions:

• The findings reveal the intricate mechanism by which the paramyxovirus fusion complex is primed for cell entry.
• The structural insights offer a detailed understanding of viral glycoprotein function and interactions.
• This work highlights potential therapeutic targets for developing novel antiviral strategies against a range of paramyxoviruses.