tetano
Editor, Senior Moderator
J Phys Chem Lett
. 2022 Jun 8;5324-5333.
doi: 10.1021/acs.jpclett.2c00967. Online ahead of print.
Structure of Human TMPRSS2 in Complex with SARS-CoV-2 Spike Glycoprotein and Implications for Potential Therapeutics
Naveen Vankadari[SUP] 1 [/SUP], Vijayasarathy Ketavarapu[SUP] 2 [/SUP], Sasikala Mitnala[SUP] 2 [/SUP], Ravikanth Vishnubotla[SUP] 2 [/SUP], Duvvur Nageshwar Reddy[SUP] 2 [/SUP], Debnath Ghosal[SUP] 3 [/SUP]
Affiliations
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 520 million people around the globe resulting in more than 6.2 million as of May 2022. Understanding the cell entry mechanism of SARS-CoV-2 and its entire repertoire is a high priority for developing improved therapeutics. The SARS-CoV-2 spike glycoprotein (S-protein) engages with host receptor ACE2 for adhesion and serine proteases furin and TMPRSS2 for proteolytic activation and subsequent entry. Recent studies have highlighted the molecular details of furin and S-protein interaction. However, the structural and molecular interplay between TMPRSS2 and S-protein remains enigmatic. Here, using biochemical, structural, computational, and molecular dynamics approaches, we investigated how TMPRSS2 recognizes and activates the S-protein to facilitate viral entry. First, we identified three potential TMPRSS2 cleavage sites in the S2 domain of S-protein (S2', T1, and T2) and reported the structure of TMPRSS2 with its individual catalytic triad. By employing computational modeling and structural analyses, we modeled the macromolecular structure of TMPRSS2 in complex with S-protein, which incited the mechanism of S-protein processing or cleavage for a new path of viral entry. On the basis of structure-guided drug screening, we also report the potential TMPRSS2 inhibitors and their structural interaction in blocking TMPRSS2 activity, which could impede the interaction with the spike protein. These findings reveal the role of TMPRSS2 in the activation of SARS-CoV-2 for its entry and insight into possible intervention strategies.
. 2022 Jun 8;5324-5333.
doi: 10.1021/acs.jpclett.2c00967. Online ahead of print.
Structure of Human TMPRSS2 in Complex with SARS-CoV-2 Spike Glycoprotein and Implications for Potential Therapeutics
Naveen Vankadari[SUP] 1 [/SUP], Vijayasarathy Ketavarapu[SUP] 2 [/SUP], Sasikala Mitnala[SUP] 2 [/SUP], Ravikanth Vishnubotla[SUP] 2 [/SUP], Duvvur Nageshwar Reddy[SUP] 2 [/SUP], Debnath Ghosal[SUP] 3 [/SUP]
Affiliations
- PMID: 35675654
- DOI: 10.1021/acs.jpclett.2c00967
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 520 million people around the globe resulting in more than 6.2 million as of May 2022. Understanding the cell entry mechanism of SARS-CoV-2 and its entire repertoire is a high priority for developing improved therapeutics. The SARS-CoV-2 spike glycoprotein (S-protein) engages with host receptor ACE2 for adhesion and serine proteases furin and TMPRSS2 for proteolytic activation and subsequent entry. Recent studies have highlighted the molecular details of furin and S-protein interaction. However, the structural and molecular interplay between TMPRSS2 and S-protein remains enigmatic. Here, using biochemical, structural, computational, and molecular dynamics approaches, we investigated how TMPRSS2 recognizes and activates the S-protein to facilitate viral entry. First, we identified three potential TMPRSS2 cleavage sites in the S2 domain of S-protein (S2', T1, and T2) and reported the structure of TMPRSS2 with its individual catalytic triad. By employing computational modeling and structural analyses, we modeled the macromolecular structure of TMPRSS2 in complex with S-protein, which incited the mechanism of S-protein processing or cleavage for a new path of viral entry. On the basis of structure-guided drug screening, we also report the potential TMPRSS2 inhibitors and their structural interaction in blocking TMPRSS2 activity, which could impede the interaction with the spike protein. These findings reveal the role of TMPRSS2 in the activation of SARS-CoV-2 for its entry and insight into possible intervention strategies.