Structural and Functional Analysis of the D614G SARS-CoV-2 Spike Protein Variant

By Leonid Yurkovetskiy, Xue Wang, Kristen E. Pascal, C. Tomkins-Tinch, Thomas Nyalile, Yetao Wang, A. Baum, W. Diehl, Ann Dauphin, C. Carbone and 12 more. Cell, 2020

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The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide, reaching near fixation in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and on cells rendered permissive by ectopic expression of human ACE2 or of ACE2 orthologs from various mammals, including Chinese rufous horseshoe bat and Malayan pangolin. D614G did not alter S protein synthesis, processing, or incorporation into SARS-CoV-2 particles, but 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 an interprotomer contact, and that the conformation is shifted towards an ACE2 binding-competent state, which is modeled to be on pathway for virion membrane fusion with target cells. Consistent with this more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated.

Subfields: Animal Science and Zoology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/71b2c9ef671b39e6e68eca579052d2362cfff5c1

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Citations in the corpus

• Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice (2021, positive): “Genomic sequencing shows that SARS-CoV-2 carrying G614 has replaced D614 as the predominant circulating variant and increases the infectivity of the virus (48, 49).”
• SARS-CoV-2 D614G Variant Exhibits Efficient Replication ex vivo and Transmission in vivo (2020, neutral): “However, we didn’t observe the enhancement of viral titers in continuous replication kinetics, suggesting the variable ACE2 and protease levels between different cell lines and the virion thermostability may also affect to the D614G replication in vitro.”