tetano
Editor, Senior Moderator
J Med Virol
. 2023 Oct;95(10):e29163.
doi: 10.1002/jmv.29163. Structural basis of the American mink ACE2 binding by Y453F trimeric spike glycoproteins of SARS-CoV-2
Hyunjun Ahn[SUP] 1 [/SUP], Brenda M Calderon[SUP] 2 3 [/SUP], Xiaoyu Fan[SUP] 2 3 [/SUP], Yunrong Gao[SUP] 1 [/SUP], Natalie L Horgan[SUP] 1 [/SUP], Nannan Jiang[SUP] 2 3 [/SUP], Dylan S Blohm[SUP] 1 [/SUP], Jaber Hossain[SUP] 2 3 [/SUP], Nicole Wedad K Rayyan[SUP] 1 [/SUP], Sarah H Osman[SUP] 2 4 [/SUP], Xudong Lin[SUP] 2 3 [/SUP], Michael Currier[SUP] 2 3 [/SUP], John Steel[SUP] 3 [/SUP], David E Wentworth[SUP] 2 3 [/SUP], Bin Zhou[SUP] 2 3 [/SUP], Bo Liang[SUP] 1 [/SUP]
Affiliations
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 receptors 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 receptors. 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 receptor 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.
Keywords: SARS-CoV-2 spike; cryo-EM structures; mink ACE2.
. 2023 Oct;95(10):e29163.
doi: 10.1002/jmv.29163. Structural basis of the American mink ACE2 binding by Y453F trimeric spike glycoproteins of SARS-CoV-2
Hyunjun Ahn[SUP] 1 [/SUP], Brenda M Calderon[SUP] 2 3 [/SUP], Xiaoyu Fan[SUP] 2 3 [/SUP], Yunrong Gao[SUP] 1 [/SUP], Natalie L Horgan[SUP] 1 [/SUP], Nannan Jiang[SUP] 2 3 [/SUP], Dylan S Blohm[SUP] 1 [/SUP], Jaber Hossain[SUP] 2 3 [/SUP], Nicole Wedad K Rayyan[SUP] 1 [/SUP], Sarah H Osman[SUP] 2 4 [/SUP], Xudong Lin[SUP] 2 3 [/SUP], Michael Currier[SUP] 2 3 [/SUP], John Steel[SUP] 3 [/SUP], David E Wentworth[SUP] 2 3 [/SUP], Bin Zhou[SUP] 2 3 [/SUP], Bo Liang[SUP] 1 [/SUP]
Affiliations
- PMID: 37842796
- DOI: 10.1002/jmv.29163
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 receptors 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 receptors. 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 receptor 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.
Keywords: SARS-CoV-2 spike; cryo-EM structures; mink ACE2.