The prefusion structure of herpes simplex virus glycoprotein B

Area of Science:

• Structural biology
• Virology
• Biochemistry

Background:

• Enveloped viruses utilize specialized fusion proteins for host cell entry.
• Herpes simplex virus 1 (HSV-1) glycoprotein B (gB) is crucial for viral fusion but is inherently unstable in its prefusion conformation.
• The metastability of prefusion gB hinders structural studies.

Purpose of the Study:

• To determine the structure of the membrane-embedded prefusion conformation of HSV-1 gB.
• To investigate conserved mechanisms of viral membrane fusion.

Main Methods:

• Identification of conserved sequence signatures in viral fusion proteins.
• Molecular dynamics simulations to design stabilizing mutations.
• Structural determination of stabilized HSV-1 gB using cryo-electron microscopy (sub-nanometer resolution).

Main Results:

• A stabilizing mutation was successfully introduced into HSV-1 gB, locking it in the prefusion state.
• The membrane-embedded prefusion structure of HSV-1 gB was elucidated at sub-nanometer resolution.
• A pseudo-atomic model revealed conserved domain rearrangements between HSV-1 gB and vesicular stomatitis virus glycoprotein G, despite distant evolutionary relationships.

Conclusions:

• The study provides a high-resolution structure of the HSV-1 gB prefusion state, a critical target for antiviral therapies.
• Conserved conformational changes in fusion proteins suggest common mechanisms across different viral classes, particularly for class III viral fusion proteins.
• These findings advance our understanding of viral fusion and offer insights into the design of novel antiviral strategies.