Prefusion structure of human cytomegalovirus glycoprotein B and structural basis for membrane fusion

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• Human cytomegalovirus (HCMV) is a significant cause of congenital disease and long-term infant morbidity.
• HCMV glycoprotein B (gB) is essential for viral entry, mediating fusion between the viral envelope and host cell membrane via a conformational transition from prefusion to postfusion states.

Purpose of the Study:

• To determine the high-resolution structure of HCMV glycoprotein B (gB) in its metastable prefusion conformation.
• To elucidate the structural mechanisms underlying membrane fusion mediated by gB.
• To provide a structural basis for the rational design of HCMV vaccine antigens.

Main Methods:

• Stabilization of prefusion gB on the virion using a fusion inhibitor and chemical cross-linking.
• Extraction and purification of stabilized prefusion gB.
• Determination of the gB structure using electron cryomicroscopy (cryo-EM) at 3.6-Å resolution.

Main Results:

• The cryo-EM structure revealed detailed interactions stabilizing prefusion gB, including those involving fusion loops, the membrane-proximal region, and the transmembrane domain.
• The structure elucidated the molecular rearrangements critical for mediating membrane fusion.
• The determined structure rationalizes known antigenic sites on gB.

Conclusions:

• The high-resolution structure of prefusion HCMV gB offers a blueprint for engineering stabilized prefusion antigens.
• This structural information can guide the development of novel HCMV vaccines aimed at eliciting protective immunity.
• The findings contribute to understanding viral entry mechanisms and developing strategies against HCMV congenital infections.