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Structural impact on SARS-CoV-2 spike protein by D614G substitution.
Science. 2021 04 30; 372(6541):525-530.Sci

Abstract

Substitution for aspartic acid (D) by glycine (G) at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. Here, we report cryo-electron microscopy structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations that differ primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer-effectively increasing the number of functional spikes and enhancing infectivity-and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.

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Authors+Show Affiliations

Zhang J
Division of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Cai Y
Division of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Xiao T
Division of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Lu J
Codex BioSolutions, Inc., Gaithersburg, MD 20879, USA.
Peng H
Division of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Sterling SM
The Harvard Cryo-EM Center for Structural Biology, Harvard Medical School, Boston, MA 02115, USA. Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Walsh RM
The Harvard Cryo-EM Center for Structural Biology, Harvard Medical School, Boston, MA 02115, USA. Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Rits-Volloch S
Division of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
Zhu H
Institute for Protein Innovation, Harvard Institutes of Medicine, Boston, MA 02115, USA.
Woosley AN
Institute for Protein Innovation, Harvard Institutes of Medicine, Boston, MA 02115, USA.
Yang W
Institute for Protein Innovation, Harvard Institutes of Medicine, Boston, MA 02115, USA.
Sliz P
Division of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Chen B
Division of Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. bchen@crystal.harvard.edu. Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.

MeSH

Amino Acid SubstitutionAngiotensin-Converting Enzyme 2Antibodies, ViralCOVID-19Cryoelectron MicroscopyHumansHydrophobic and Hydrophilic InteractionsModels, MolecularMutant ProteinsProtein BindingProtein ConformationProtein DomainsProtein SubunitsReceptors, CoronavirusSARS-CoV-2Spike Glycoprotein, CoronavirusVirus Internalization

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

33727252

Citation

Zhang, Jun, et al. "Structural Impact On SARS-CoV-2 Spike Protein By D614G Substitution." Science (New York, N.Y.), vol. 372, no. 6541, 2021, pp. 525-530.
Zhang J, Cai Y, Xiao T, et al. Structural impact on SARS-CoV-2 spike protein by D614G substitution. Science. 2021;372(6541):525-530.
Zhang, J., Cai, Y., Xiao, T., Lu, J., Peng, H., Sterling, S. M., Walsh, R. M., Rits-Volloch, S., Zhu, H., Woosley, A. N., Yang, W., Sliz, P., & Chen, B. (2021). Structural impact on SARS-CoV-2 spike protein by D614G substitution. Science (New York, N.Y.), 372(6541), 525-530. https://doi.org/10.1126/science.abf2303
Zhang J, et al. Structural Impact On SARS-CoV-2 Spike Protein By D614G Substitution. Science. 2021 04 30;372(6541):525-530. PubMed PMID: 33727252.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural impact on SARS-CoV-2 spike protein by D614G substitution. AU - Zhang,Jun, AU - Cai,Yongfei, AU - Xiao,Tianshu, AU - Lu,Jianming, AU - Peng,Hanqin, AU - Sterling,Sarah M, AU - Walsh,Richard M,Jr AU - Rits-Volloch,Sophia, AU - Zhu,Haisun, AU - Woosley,Alec N, AU - Yang,Wei, AU - Sliz,Piotr, AU - Chen,Bing, Y1 - 2021/03/16/ PY - 2020/10/12/received PY - 2021/03/10/accepted PY - 2021/3/18/pubmed PY - 2021/5/8/medline PY - 2021/3/17/entrez SP - 525 EP - 530 JF - Science (New York, N.Y.) JO - Science VL - 372 IS - 6541 N2 - Substitution for aspartic acid (D) by glycine (G) at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. Here, we report cryo-electron microscopy structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations that differ primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer-effectively increasing the number of functional spikes and enhancing infectivity-and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development. SN - 1095-9203 UR - https://www.unboundmedicine.com/medline/citation/33727252/Structural_impact_on_SARS_CoV_2_spike_protein_by_D614G_substitution_ DB - PRIME DP - Unbound Medicine ER -