Molecular docking between human TMPRSS2 and SARS-CoV-2 spike protein: conformation and intermolecular interactions

Mushtaq Hussain; Nusrat Jabeen; Anusha Amanullah; Ayesha Ashraf Baig; Basma Aziz; Sanya Shabbir; Fozia Raza; Nasir Uddin; Mushtaq Hussain; Nusrat Jabeen; Anusha Amanullah; Ayesha Ashraf Baig; Basma Aziz; Sanya Shabbir; Fozia Raza; Nasir Uddin

doi:10.3934/microbiol.2020021

AIMS Microbiology

2020, Volume 6, Issue 3: 350-360. doi: 10.3934/microbiol.2020021

Previous Article Next Article

Research article

Molecular docking between human TMPRSS2 and SARS-CoV-2 spike protein: conformation and intermolecular interactions

1.
Bioinformatics and Molecular Medicine Research Group, Dow Research Institute of Biotechnology and Biomedical Sciences, Dow College of Biotechnology, Dow University of Health Sciences, Karachi-Pakistan
2.
Department of Microbiology, University of Karachi, Karachi-Pakistan
3.
Faculty of Computer Science, IBA, Karachi-Pakistan

Received: 17 July 2020 Accepted: 21 September 2020 Published: 24 September 2020

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 attributes of the molecular complex between TMPRSS2 and SARS-CoV-2 spike protein, in order to discern the finer details of the priming of viral spike protein. 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 provides 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.
- SARS-CoV-2,
- COVID-19,
- spike protein,
- TMPRSS2,
- molecular docking
Citation: Mushtaq Hussain, Nusrat Jabeen, Anusha Amanullah, Ayesha Ashraf Baig, Basma Aziz, Sanya Shabbir, Fozia Raza, Nasir Uddin. Molecular docking between human TMPRSS2 and SARS-CoV-2 spike protein: conformation and intermolecular interactions[J]. AIMS Microbiology, 2020, 6(3): 350-360. doi: 10.3934/microbiol.2020021

Related Papers:

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 attributes of the molecular complex between TMPRSS2 and SARS-CoV-2 spike protein, in order to discern the finer details of the priming of viral spike protein. 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 provides 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.

Acknowledgments

The study is supported by Higher Education Commission, Pakistan.

Conflict of Interest

All authors declare no conflicts of interest in this paper.

References

[1]	Cui J, Li F, Shi ZL (2019) Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 17: 181-192. doi: 10.1038/s41579-018-0118-9
[2]	https://covid19.who.int/.
[3]	Wu A, Peng Y, Huang B, et al. (2020) Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China. Cell Host Microbe 27: 325-328. doi: 10.1016/j.chom.2020.02.001
[4]	Li F (2015) Receptor recognition mechanisms of coronaviruses: a decade of structural studies. J Virol 89: 1954-1964. doi: 10.1128/JVI.02615-14
[5]	Lan J, Ge J, Yu J, et al. (2020) Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581: 215-220. doi: 10.1038/s41586-020-2180-5
[6]	Hoffmann M, Kleine-Weber H, Schroeder, et al. (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181: 271-280. doi: 10.1016/j.cell.2020.02.052
[7]	Wang Q, Qiu Y, Li JY, et al. (2020) A unique protease cleavage site predicted in the spike protein of the novel pneumonia coronavirus (2019-nCoV) potentially related to viral transmissibility. Virol Sin 35: 337-339. doi: 10.1007/s12250-020-00212-7
[8]	Zhang H, Penninger JM, Li Y, et al. (2020) Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 46: 586-590. doi: 10.1007/s00134-020-05985-9
[9]	Wrapp D, Wang N, Corbett KS, et al. (2020) Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367: 1260-1263. doi: 10.1126/science.abb2507
[10]	Herter S, Piper DE, Aaron W, et al. (2005) Hepatocyte growth factor is a preferred in vitro substrate for human hepsin, a membrane-anchored serine protease implicated in prostate and ovarian cancers. Biochem J 390: 125-136. doi: 10.1042/BJ20041955
[11]	Goodsell DS, Zardecki C, Di Costanzo L, et al. (2020) RCSB Protein Data Bank: Enabling biomedical research and drug discovery. Protein Sci 29: 52-65. doi: 10.1002/pro.3730
[12]	Slabinski L, Jaroszewski L, Rychlewski L, et al. (2007) XtalPred: a web server for prediction of protein crystallizability. Bioinformatics 23: 3403-3405. doi: 10.1093/bioinformatics/btm477
[13]	Roy A, Kucukural A, Zhang Y (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5: 725. doi: 10.1038/nprot.2010.5
[14]	Webb B, Sali A (2016) Comparative protein structure modeling using MODELLER. Curr Protoc Bioinformatics 54: 5-6. doi: 10.1002/cpbi.3
[15]	Chen VB, Arendall WB, Headd JJ, et al. (2010) MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr 66: 12-21. doi: 10.1107/S0907444909042073
[16]	Wiederstein M, Sippl MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res 35: W407-410. doi: 10.1093/nar/gkm290
[17]	Johansson MU, Zoete V, Michielin O, et al. (2012) Defining and searching for structural motifs using DeepView/Swiss-PdbViewer. BMC Bioinform 13: 173. doi: 10.1186/1471-2105-13-173
[18]	Abraham MJ, Murtola T, Schulz R, et al. (2015) GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1: 19-25. doi: 10.1016/j.softx.2015.06.001
[19]	Van Zundert GC, Rodrigues JP, Trellet M, et al. (2016) The HADDOCK2. 2 web server: user-friendly integrative modeling of biomolecular complexes. J Mol Biol 428: 720-725. doi: 10.1016/j.jmb.2015.09.014
[20]	Xue LC, Rodrigues JP, Kastritis PL, et al. (2016) PRODIGY: a web server for predicting the binding affinity of protein–protein complexes. Bioinformatics 32: 3676-3678.
[21]	Paoloni-Giacobino A, Chen H, Peitsch MC, et al. (1997) Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22. 3. Genomics 44: 309-320. doi: 10.1006/geno.1997.4845
[22]	Ojala JR, Pikkarainen T, Tuuttila A, et al. (2007) Crystal structure of the cysteine-rich domain of scavenger receptor MARCO reveals the presence of a basic and an acidic cluster that both contribute to ligand recognition. J Biol Chem 282: 16654-16666. doi: 10.1074/jbc.M701750200
[23]	Mönttinen HA, Ravantti JJ, Poranen MM (2019) Structural comparison strengthens the higher-order classification of proteases related to chymotrypsin. PLoS One 14: e0216659. doi: 10.1371/journal.pone.0216659
[24]	Böttcher E, Matrosovich T, Beyerle M, et al. (2006) Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol 80: 9896-9898. doi: 10.1128/JVI.01118-06
[25]	Shirogane Y, Takeda M, Iwasaki M, et al. (2008) Efficient multiplication of human metapneumovirus in Vero cells expressing the transmembrane serine protease TMPRSS2. J Virol 82: 8942-8946. doi: 10.1128/JVI.00676-08
[26]	Vaarala MH, Porvari KS, Kellokumpu S, et al. (2001) Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues. J Pathol 193: 134-140. doi: 10.1002/1096-9896(2000)9999:9999<::AID-PATH743>3.0.CO;2-T
[27]	Zhou L, Xu Z, Castiglione GM, et al. (2020) ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection. Ocul Surf 18: 537-544. doi: 10.1016/j.jtos.2020.06.007
[28]	Afar DE, Vivanco I, Hubert RS, et al. (2001) Catalytic cleavage of the androgen-regulated TMPRSS2 protease results in its secretion by prostate and prostate cancer epithelia. Cancer Res 61: 1686-1692.
[29]	Donaldson SH, Hirsh A, Li DC, et al. (2002) Regulation of the epithelial sodium channel by serine proteases in human airways. J Biol Chem 277: 8338-8345. doi: 10.1074/jbc.M105044200
[30]	Aimes RT, Zijlstra A, Hooper JD, et al. (2003) Endothelial cell serine proteases expressed during vascular morphogenesis and angiogenesis. J Thromb Haemost 89: 561-572. doi: 10.1055/s-0037-1613388
[31]	Shulla A, Heald-Sargent T, Subramanya G, et al. (2011) A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. J Virol 85: 873-882. doi: 10.1128/JVI.02062-10
[32]	Abe M, Tahara M, Sakai K, et al. (2013) TMPRSS2 is an activating protease for respiratory parainfluenza viruses. J Virol 87: 11930-11935. doi: 10.1128/JVI.01490-13
[33]	Shirato K, Kawase M, Matsuyama S (2013) Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2. J Virol 87: 12552-12561. doi: 10.1128/JVI.01890-13
[34]	Shah B, Modi P, Sagar SR (2020) In silico studies on therapeutic agents for COVID-19: Drug repurposing approach. Life Sci e117652. doi: 10.1016/j.lfs.2020.117652
[35]	Hussain M (2013) Phylogenomic and structure-function relationship studies of proteins involved in EBV associated oncogenesis. University of Glasgow 84: 2209-2217.
[36]	Araghi RR, Keating AE (2016) Designing helical peptide inhibitors of protein–protein interactions. Curr Opin Struct Biol 39: 27-38. doi: 10.1016/j.sbi.2016.04.001
[37]	Cardinale D, Guaitoli G, Tondi D, et al. (2011) Protein–protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase. PNAS 108: E542-E549. doi: 10.1073/pnas.1104829108
[38]	Hussain M, Jabeen N, Raza F, et al. (2020) Structural Variations in Human ACE2 may Influence its Binding with SARS-CoV-2 Spike Protein. J Med Virol 92: 1580-1586. doi: 10.1002/jmv.25832
[39]	Zang R, Castro MF, McCune BT, et al. (2020) TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol 5: eabc3582. doi: 10.1126/sciimmunol.abc3582
[40]	Hoffmann M, Kleine-Weber H, Pöhlmann SA (2020) Multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells. Mol Cell 78: 779-784. doi: 10.1016/j.molcel.2020.04.022

Reader Comments

Your name:*

Email:*
© 2020 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)