Structural Basis of SARS-CoV-2 Spike Protein Priming by TMPRSS2

  1. Mushtaq Hussain
  2. Nusrat Jabeen
  3. Anusha Amanullah
  4. Ayesha Ashraf Baig
  5. Basma Aziz
  6. Sanya Shabbir
  7. Fozia Raza

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Abstract

Entry of SARS-CoV-2, etiological agent of COVID-19, in the host cell is driven by the interaction of its spike protein with human ACE2 receptor and a serine protease, TMPRSS2. Although complex between SARS-CoV-2 spike protein and ACE2 has been structurally resolved, the molecular details of the SARS-CoV-2 and TMPRSS2 complex are still elusive. TMPRSS2 is responsible for priming of the viral spike protein that entails cleavage of the spike protein at two potential sites, Arg685/Ser686 and Arg815/Ser816. The present study aims to investigate the conformational details of complex between TMPRSS2 and SARS-CoV-2 spike protein, in order to discern the finer details of the priming of viral spike and to point candidate drug targets. Briefly, full length structural model of TMPRSS2 was developed and docked against the resolved structure of SARS-CoV-2 spike protein with directional restraints of both cleavage sites. The docking simulations showed that TMPRSS2 interacts with the two different loops of SARS-CoV-2 spike protein, each containing different cleavage sites. Key functional residues of TMPRSS2 (His296, Ser441 and Ser460) were found to interact with immediate flanking residues of cleavage sites of SARS-CoV-2 spike protein. Compared to the N-terminal cleavage site (Arg685/Ser686), TMPRSS2 region that interact with C-terminal cleavage site (Arg815/Ser816) of the SARS-CoV-2 spike protein was predicted as relatively more druggable. In summary, the present study provide structural characteristics of molecular complex between human TMPRSS2 and SARS-CoV-2 spike protein and points to the candidate drug targets that could further be exploited to direct structure base drug designing.

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  1. ScreenIT

    SciScore for 10.1101/2020.04.21.052639: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Data mining for structures: Protein sequence of human TMPRSS2 (O15393) was retrieved from UniProt and subjected to PDB Blast to identify the homologous structure on the basis of query coverage and sequence identity.
    UniProt
    suggested: (UniProtKB, RRID:SCR_004426)
    Since, hepsin molecule was found to share noticeable homology with the SRCR and peptidase S1 domains of TMPRSS2, a full length model of TMPRSS2 were later developed using Modeller 9.16 (Webb and Sali, 2016) taking model developed by I-TASSER and hepsin (PDBid: 1Z8G) as templates.
    Modeller
    suggested: (MODELLER, RRID:SCR_008395)
    I-TASSER
    suggested: (I-TASSER, RRID:SCR_014627)
    The structural quality of the model was assessed by MolProbity for Ramachandran Plot (Chen et al., 2010) and ProSA (Wiederstein and Sippl, 2007).
    MolProbity
    suggested: (MolProbity, RRID:SCR_014226)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 15. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

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  2. Version published to 10.1101/2020.04.21.052639 on bioRxiv
  3. Version published to 10.3934/microbiol.2020021