OmniVira

Effect of natural mutations of SARS-CoV-2 on spike structure, conformation, and antigenicity.

Sophie M-C Gobeil1 Katarzyna Janowska1 Shana McDowell1 Katayoun Mansouri1 Robert Parks1 Victoria Stalls1 Megan F Kopp1 Kartik Manne1 Dapeng Li1 Kevin Wiehe1,2 Kevin O Saunders1,3,4,5 Robert J Edwards1,2 Bette Korber6 Barton F Haynes1,2,5 Rory Henderson7,2 Priyamvada Acharya7,3,8
Affiliations 8 institutions
  1. Duke Human Vaccine Institute, Durham, NC 27710, USA.
  2. Department of Medicine, Duke University, Durham, NC 27710, USA.
  3. Department of Surgery, Duke University, Durham, NC 27710, USA.
  4. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
  5. Department of Immunology, Duke University, Durham, NC 27710, USA.
  6. Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
  7. Duke Human Vaccine Institute, Durham, NC 27710, USA. [email protected] [email protected].
  8. Department of Biochemistry, Duke University, Durham, NC 27710, USA.
PMID34168071 DOI10.1126/science.abi6226 Year2021 Journal Science (New York, N.Y.) Science Languageeng Statusppublish

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with multiple spike mutations enable increased transmission and antibody resistance. We combined cryo-electron microscopy (cryo-EM), binding, and computational analyses to study variant spikes, including one that was involved in transmission between minks and humans, and others that originated and spread in human populations. All variants showed increased angiotensin-converting enzyme 2 (ACE2) receptor binding and increased propensity for receptor binding domain (RBD)-up states. While adaptation to mink resulted in spike destabilization, the B.1.1.7 (UK) spike balanced stabilizing and destabilizing mutations. A local destabilizing effect of the RBD E484K mutation was implicated in resistance of the B.1.1.28/P.1 (Brazil) and B.1.351 (South Africa) variants to neutralizing antibodies. Our studies revealed allosteric effects of mutations and mechanistic differences that drive either interspecies transmission or escape from antibody neutralization.

Supporting text Virus Host Location
Amino Acid Substitution 81 Angiotensin-Converting Enzyme 2 177 Animals 1948 Antibodies, Neutralizing 80 Antibodies, Viral 212 Antigens, Viral 49 COVID-19 425 Cryoelectron Microscopy 37 Host Adaptation 7 Humans 1440 Immune Evasion 25 Mink 48 Models, Molecular 99 Mutation 209 Protein Binding 193 Protein Conformation 44 Protein Interaction Domains and Motifs 12 Protein Structure, Quaternary 5 Protein Subunits 3 Receptors, Coronavirus 6 SARS-CoV-2 453 Spike Glycoprotein, Coronavirus 274 ACE2 protein, human 87 spike protein, SARS-CoV-2 157

Evidence records

2 total
Functional Mechanism
2 records · 1 evidence types
Evidence type Molecular Adaptation
2 records
OVE4903 Molecular Adaptation
Key finding

The RBD E484K mutation in SARS-CoV-2 variants B.1.1.28/P.1 and B.1.351 led to local spike destabilization and escape from neutralizing antibodies.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

A local destabilizing effect of the RBD E484K mutation was implicated in resistance of the B.1.1.28/P.1 (Brazil) and B.1.351 (South Africa) variants to neutralizing antibodies.

Genes or proteins
spike | RBD
Receptors
ACE2
Mutations
E484K
Mechanism types
immune escape | receptor binding
OVE4902 Molecular Adaptation
Key finding

Adaptation of SARS-CoV-2 to minks caused spike protein destabilization, indicating molecular adaptation during interspecies transmission.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

While adaptation to mink resulted in spike destabilization, the B.1.1.7 (UK) spike balanced stabilizing and destabilizing mutations.

Genes or proteins
spike
Receptors
ACE2
Mechanism types
host-range expansion | transmission fitness | receptor binding