9Q4F

Measles Virus Fusion Glycoprotein Postfusion Core (Wild-type Variant)

Summary for 9Q4F

• Entry DOI: 10.2210/pdb9q4f/pdb
• Descriptor: Fusion glycoprotein F1 N-terminal heptad repeat (HR1), Fusion glycoprotein F1 C-terminal heptad repeat (HR2), BROMIDE ION, ... (4 entities in total)
• Functional Keywords: measles, fusion glycoprotein, wild-type, six helix bundle, viral protein
• Biological source: Measles morbillivirus; More
• Total number of polymer chains: 12
• Total formula weight: 55385.28

Authors

Vithanage, N.,Outlaw, V.K. (deposition date: 2025-08-20, release date: 2026-08-05, Last modification date: 2026-08-12)

Primary citation

Vithanage, N.,Outlaw, V.K.
Hyperfusogenic Mutations Destabilize the Postfusion Six-Helix Bundle of the Measles Virus Fusion Glycoprotein.
Biochemistry, 65:2350-2358, 2026

PubMed Abstract: Fusion of the host membrane and viral envelope by class I viral fusion proteins is driven by the assembly of a postfusion six-helix bundle formed through antiparallel interactions between N-terminal (HR1) and C-terminal (HR2) heptad-repeat regions. Although mutations in these regions of the measles virus (MeV) fusion (F) glycoprotein are known to promote neuropathogenic and hyperfusogenic phenotypes, their effects on postfusion core stability have not been systematically examined. Here, we combine peptide biophysics and X-ray crystallography to interrogate how mutations within the HR2 domain, present in native neuropathogenic MeV isolates (e.g., L454W and N462K) and laboratory-generated hyperfusogenic variants (e.g., L454M and T461A), influence postfusion 6HB assembly. Circular dichroism (CD) spectroscopy reveals that, with few exceptions, these mutations decrease postfusion core stability, despite their association with enhanced fusion activity. We also report the first crystal structure of the wild-type MeV postfusion core as well as structures of six hyperfusogenic variants, enabling high-resolution comparison of the molecular basis of destabilization. Structural analysis shows that these effects arise from localized perturbations to steric packing, hydrogen bonding networks, and helix-stabilizing interactions within HR2, while the overall 6HB architecture remains conserved. Together, these results indicate that hyperfusogenic mutations are not associated with stabilization of the postfusion state and are instead consistent with models in which hyperfusogenicity arises from a reduction in the energetic barrier to fusion, potentially through effects on prefusion stability or triggering efficiency. These findings establish key sequence-structure-stability relationships governing coiled-coil assembly and provide a framework for the design of HR1- and HR2-based fusion inhibitors.

PubMed: 42485314
DOI: 10.1021/acs.biochem.6c00182

Experimental method

X-RAY DIFFRACTION (1.95 Å)