A glycan gate controls opening of the SARS-CoV-2 spike protein.

Autor:	Sztain T; Department of Chemistry and Biochemistry, UC San Diego, La Jolla, CA 92093., Ahn SH; Department of Chemistry and Biochemistry, UC San Diego, La Jolla, CA 92093., Bogetti AT; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260., Casalino L; Department of Chemistry and Biochemistry, UC San Diego, La Jolla, CA 92093., Goldsmith JA; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712., Seitz E; Department of Biological Sciences, Columbia University, New York, NY, 10032, USA., McCool RS; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712., Kearns FL; Department of Chemistry and Biochemistry, UC San Diego, La Jolla, CA 92093., Acosta-Reyes F; Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA., Maji S; Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA., Mashayekhi G; Department of Physics, University of Wisconsin-Milwaukee, 3135 N. Maryland Ave, Milwaukee, WI 53211, USA., McCammon JA; Department of Chemistry and Biochemistry, UC San Diego, La Jolla, CA 92093.; Department of Pharmacology, UC San Diego, La Jolla, CA 92093., Ourmazd A; Department of Physics, University of Wisconsin-Milwaukee, 3135 N. Maryland Ave, Milwaukee, WI 53211, USA., Frank J; Department of Biological Sciences, Columbia University, New York, NY, 10032, USA.; Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA., McLellan JS; Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712., Chong LT; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260., Amaro RE; Department of Chemistry and Biochemistry, UC San Diego, La Jolla, CA 92093.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2021 May 17. Date of Electronic Publication: 2021 May 17.
DOI:	10.1101/2021.02.15.431212
Abstrakt:	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 in order to bind the human ACE2 receptor and infect cells. While snapshots of the "up" and "down" states have been obtained by cryoEM and cryoET, details of the RBD opening transition evade experimental characterization. Here, over 130 μs of weighted ensemble (WE) 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-EM 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 achieves a new high-water mark for ensemble pathway simulations and offers a foundation for understanding the fundamental mechanisms of SARS-CoV-2 viral entry and infection. Competing Interests: Competing interests statement The authors declare no competing financial interests.
Databáze:	MEDLINE
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