Related Experiment Video
Updated: Dec 15, 2025
High-throughput Confocal Imaging of Quantum Dot-Conjugated SARS-CoV-2 Spike Trimers to Track Binding and Endocytosis in HEK293T Cells
Published on: April 21, 2022
Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant
Leonid Yurkovetskiy1,2, Xue Wang3,2, Kristen E Pascal4
1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Abstract:
The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and cells rendered permissive by ectopic expression of various mammalian ACE2 orthologs. Nonetheless, D614G affinity for ACE2 was reduced due to a faster dissociation rate. Assessment of the S protein trimer by cryo-electron microscopy showed that D614G disrupts a critical interprotomer contact and that this dramatically shifts the S protein trimer conformation toward an ACE2-binding and fusion-competent state. Consistent with the more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated. These results indicate that D614G adopts conformations that make virion membrane fusion with the target cell membrane more probable but that D614G retains susceptibility to therapies that disrupt interaction of the SARS-CoV-2 S protein with the ACE2 receptor.
Insights
The SARS-CoV-2 D614G spike protein variant is more infectious due to a more open conformation, enhancing cell entry. However, it remains susceptible to therapies targeting the ACE2 receptor interaction.
Area of Science:
- Virology
- Structural Biology
- Molecular Biology
Background:
- The SARS-CoV-2 D614G spike (S) protein variant rapidly became globally dominant over the ancestral strain.
- Understanding the molecular mechanisms driving the D614G variant's increased infectivity is crucial for developing effective therapeutics.
Approach:
- Investigated the infectivity of the D614G variant on various human cell types, including lung and colon cells.
- Utilized cryo-electron microscopy to analyze the structural conformation of the S protein trimer in the D614G variant.
- Assessed the binding affinity of the D614G variant to the human ACE2 receptor and its susceptibility to antibody neutralization.
Key Points:
- The D614G variant exhibits enhanced infectivity across multiple human cell types.
- Structural analysis revealed that D614G disrupts interprotomer contacts, favoring an ACE2-binding and fusion-competent conformation.
- Despite reduced ACE2 binding affinity due to faster dissociation, the altered conformation facilitates viral entry.
Conclusions:
- The D614G variant's conformational changes promote more efficient virion membrane fusion with target cells.
- Antibody neutralization potency against the receptor-binding domain remains effective, indicating retained susceptibility to existing therapies.
- These findings provide insights into viral evolution and inform strategies for combating SARS-CoV-2.
Related Concept Videos
02:50Conjugated Proteins
Nucleoproteins are protein complexes that contain nucleic acids, categorized as deoxyribonucleoproteins (DNPs) or ribonucleoproteins (RNPs) respectively. The nucleosome is a typical example of a DNP where nuclear DNA is associated with histone proteins. The major antigen for the Covid-19 virus SARS-CoV is an RNP that is critical...
00:56Viral Structure
01:56Structural Protein Function
01:56Structural Protein Function
Collagen, the most abundant protein in mammals, is found throughout the body. In connective tissue, such as skin, ligaments, and tendons, it provides tensile strength and elasticity. In bones and teeth, it mineralizes to...
02:28Leaky Scanning
01:26Size and Structure of Viral Genomes