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Structural basis of the American mink ACE2 binding by Y453F trimeric spike glycoproteins of SARS-CoV-2
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  • Bo Liang,
  • Hyunjun Ahn,
  • Brenda M. Calderon,
  • Xiaoyu Fan,
  • Yunrong Gao,
  • Natalie L. Horgan,
  • Nannan Jiang,
  • Dylan S. Blohm,
  • Jaber Hossain,
  • Nicole Wedad K. Rayyan,
  • Sarah H. Osman,
  • Xudong Lin,
  • Michael Currier,
  • John Steel,
  • David E. Wentworth,
  • Bin Zhou
Bo Liang
Emory University Department of Biochemistry

Corresponding Author:bo.liang@emory.edu

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Hyunjun Ahn
Emory University Department of Biochemistry
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Brenda M. Calderon
Centers for Disease Control and Prevention
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Xiaoyu Fan
Centers for Disease Control and Prevention
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Yunrong Gao
Emory University Department of Biochemistry
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Natalie L. Horgan
Emory University Department of Biochemistry
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Nannan Jiang
Centers for Disease Control and Prevention
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Dylan S. Blohm
Emory University Department of Biochemistry
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Jaber Hossain
Centers for Disease Control and Prevention
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Nicole Wedad K. Rayyan
Emory University Department of Biochemistry
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Sarah H. Osman
Centers for Disease Control and Prevention
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Xudong Lin
Centers for Disease Control and Prevention
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Michael Currier
Centers for Disease Control and Prevention
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John Steel
National Center for Immunization and Respiratory Diseases
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David E. Wentworth
Centers for Disease Control and Prevention
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Bin Zhou
Centers for Disease Control and Prevention
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Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) enters the host cell by binding to angiotensin-converting enzyme 2 (ACE2). While evolutionarily conserved, ACE2 glycoproteins differ across various species and differential interactions with Spike (S) glycoproteins of SARS-CoV-2 viruses impact species specificity. Reverse zoonoses led to SARS-CoV-2 outbreaks on multiple American mink ( Mustela vison) farms during the pandemic and gave rise to mink-associated S substitutions known for transmissibility between mink and zoonotic transmission to humans. In this study, we used bio-layer interferometry (BLI) to discern the differences in binding affinity between multiple human and mink-derived S glycoproteins of SARS-CoV-2 and their respective ACE2 glycoproteins. Further, we conducted a structural analysis of a mink variant S glycoprotein and American mink ACE2 (mvACE2) using cryo-electron microscopy (cryo-EM), revealing four distinct conformations. We discovered a novel intermediary conformation where the mvACE2 glycoprotein is bound to the receptor-binding domain (RBD) of the S glycoprotein in a “down” position, approximately 34° lower than previously reported “up” RBD. Finally, we compared residue interactions in the S-ACE2 complex interface of S glycoprotein conformations with varying RBD orientations. These findings provide valuable insights into the molecular mechanisms of SARS-CoV-2 entry.
31 Jul 2023Submitted to Journal of Medical Virology
31 Jul 2023Submission Checks Completed
31 Jul 2023Assigned to Editor
31 Jul 2023Review(s) Completed, Editorial Evaluation Pending
31 Jul 2023Reviewer(s) Assigned
22 Aug 2023Editorial Decision: Revise Major
27 Sep 20231st Revision Received
28 Sep 2023Submission Checks Completed
28 Sep 2023Assigned to Editor
28 Sep 2023Review(s) Completed, Editorial Evaluation Pending
28 Sep 2023Editorial Decision: Accept