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A glycan gate controls opening of the SARS-CoV-2 spike protein.
Sztain, Terra; Ahn, Surl-Hee; Bogetti, Anthony T; Casalino, Lorenzo; Goldsmith, Jory A; Seitz, Evan; McCool, Ryan S; Kearns, Fiona L; Acosta-Reyes, Francisco; Maji, Suvrajit; Mashayekhi, Ghoncheh; McCammon, J Andrew; Ourmazd, Abbas; Frank, Joachim; McLellan, Jason S; Chong, Lillian T; Amaro, Rommie E.
  • Sztain T; Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, CA, USA.
  • Ahn SH; Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, CA, USA.
  • Bogetti AT; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
  • Casalino L; Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, CA, USA.
  • Goldsmith JA; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.
  • Seitz E; Department of Biological Sciences, Columbia University, New York, NY, USA.
  • McCool RS; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.
  • Kearns FL; Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, CA, USA.
  • Acosta-Reyes F; Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY, USA.
  • Maji S; Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY, USA.
  • Mashayekhi G; Department of Physics, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
  • McCammon JA; Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, CA, USA.
  • Ourmazd A; Department of Pharmacology, University of California-San Diego, La Jolla, CA, USA.
  • Frank J; Department of Physics, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
  • McLellan JS; Department of Biological Sciences, Columbia University, New York, NY, USA.
  • Chong LT; Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY, USA.
  • Amaro RE; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX, USA.
Nat Chem ; 13(10): 963-968, 2021 10.
Article in English | MEDLINE | ID: covidwho-1366819
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ABSTRACT
SARS-CoV-2 infection is controlled by the opening of the spike protein receptor binding domain (RBD), which transitions from a glycan-shielded 'down' to an exposed 'up' state to bind the human angiotensin-converting enzyme 2 receptor and infect cells. While snapshots of the 'up' and 'down' states have been obtained by cryo-electron microscopy and cryo-electron tomagraphy, details of the RBD-opening transition evade experimental characterization. Here over 130 µs of weighted ensemble simulations of the fully glycosylated spike ectodomain allow us to characterize more than 300 continuous, kinetically unbiased RBD-opening pathways. Together with ManifoldEM analysis of cryo-electron microscopy data and biolayer interferometry experiments, we reveal a gating role for the N-glycan at position N343, which facilitates RBD opening. Residues D405, R408 and D427 also participate. The atomic-level characterization of the glycosylated spike activation mechanism provided herein represents a landmark study for ensemble pathway simulations and offers a foundation for understanding the fundamental mechanisms of SARS-CoV-2 viral entry and infection.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Polysaccharides / Spike Glycoprotein, Coronavirus Type of study: Experimental Studies Limits: Humans Language: English Journal: Nat Chem Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: S41557-021-00758-3

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Polysaccharides / Spike Glycoprotein, Coronavirus Type of study: Experimental Studies Limits: Humans Language: English Journal: Nat Chem Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: S41557-021-00758-3