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Cryo-EM Structures of SARS-CoV-2 Spike without and with ACE2 Reveal a pH-Dependent Switch to Mediate Endosomal Positioning of Receptor-Binding Domains

  1. Author:
    Zhou, Tongqing
    Tsybovsky,Yaroslav
    Gorman, Jason
    Rapp, Micah
    Cerutti, Gabriele
    Chuang, Gwo-Yu
    Katsamba, Phinikoula S
    Sampson, Jared M
    Schön, Arne
    Bimela, Jude
    Boyington, Jeffrey C
    Nazzari, Alexandra
    Olia, Adam S
    Shi, Wei
    Sastry, Mallika
    Stephens,Tyler
    Stuckey, Jonathan
    Teng, I-Ting
    Wang, Pengfei
    Wang, Shuishu
    Zhang, Baoshan
    Friesner, Richard A
    Ho, David D
    Mascola, John R
    Shapiro, Lawrence
    Kwong, Peter D

  2. Author Address

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA., Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Chemistry, Columbia University, New York, NY 10027, USA., Department of Biology, Johns Hopkins University, Baltimore, MD, 21218, USA., Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA., Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: lss8@columbia.edu., Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. Electronic address: pdkwong@nih.gov.,
    1. Year: 2020
    2. Date: Dec 9
    3. Epub Date: 2020 11 17
  2. Journal: Cell Host & Microbe
    1. 28
    2. Pages: 867-+
  4. Type of Article: Article
  5. ISSN: 1931-3128
  1. Abstract:

    The SARS-CoV-2 spike employs mobile receptor-binding domains (RBDs) to engage the human ACE2 receptor and to facilitate virus entry, which can occur through low-pH-endosomal pathways. To understand how ACE2 binding and low pH affect spike conformation, we determined cryo-electron microscopy structures-at serological and endosomal pH-delineating spike recognition of up to three ACE2 molecules. RBDs freely adopted "up" conformations required for ACE2 interaction, primarily through RBD movement combined with smaller alterations in neighboring domains. In the absence of ACE2, single-RBD-up conformations dominated at pH 5.5, resolving into a solitary all-down conformation at lower pH. Notably, a pH-dependent refolding region (residues 824-858) at the spike-interdomain interface displayed dramatic structural rearrangements and mediated RBD positioning through coordinated movements of the entire trimer apex. These structures provide a foundation for understanding prefusion-spike mechanics governing endosomal entry; we suggest that the low pH all-down conformation potentially facilitates immune evasion from RBD-up binding antibody. Published by Elsevier Inc.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.chom.2020.11.004
  3. PMID: 33271067
  4. View record in Web of Science®
  5. WOS: 000597360400013
  6. PII : S1931-3128(20)30621-1

Library Notes

  1. Fiscal Year: FY2020-2021
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