Abstract
The 2019 coronavirus disease (COVID-19) pandemic continues to challenge health care systems worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for the cause of global pandemic. Type 2 transmembrane serine protease (TMPRSS2) is important in the cell entry and spread of SARS-CoV-2 and plays a crucial role in the proteolytic cleavage of SARS-CoV-2 spike (S) glycoprotein. Here, using reported structural data, we analyzed the molecular complex of TMPRSS2 and the S glycoprotein and further examined intermolecular interactions of natural TMPRSS2 polymorphic variants. We identified several TMPRSS2 variants that could possibly alter host susceptibility to the SARS-CoV-2 infection. Molecular docking analysis revealed that G462D/G462S variants were predicted to be protective variants, whereas Q438E and S339F variants were predicted to increase susceptibility. In addition, we examined intermolecular interactions between TMPRSS2 and its two potential serine protease inhibitors, camostat mesylate and nafamostat. Further, we investigated the effect of TMPRSS2 variants on these interactions. Our structural analysis revealed that G462D, C297S and S460R variants had possibly altered the interactions with the protease inhibitors. Our results identified important TMPRSS2 variations that could be useful to develop high affinity and personalized drugs for treating COVID-19 patients.
Highlights
The current global coronavirus disease 2019 (COVID-19) pandemic, which is being caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant health burden and infected more than 331 million people, with more than 5.5 million deaths worldwide
In order to understand the mechanism of inhibition exhibited by these serine protease inhibitors, detailed intermolecular interactions between the protein inhibitors and TMPRSS2 are crucial
The ectodomain is comprised of three subdomains: a low-density lipoprotein receptor type A (LDLR-A) domain, a class A scavenger receptor cysteine-rich (SRCR) domain and a trypsin-like serine peptidase
Summary
The current global coronavirus disease 2019 (COVID-19) pandemic, which is being caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant health burden and infected more than 331 million people, with more than 5.5 million deaths worldwide (as of January 2022, WHO). The SARS-CoV-2 S glycoprotein and its receptor ACE2 as well as the protease TMPRSS2 play major roles in the viral infection and immune evasion. Gender-specific differences between males and females that exhibit sexual dimorphism contribute to different susceptibility to the infection, disease progression and treatment [22] While both sexes have the same COVID-19 prevalence, men with the disease are more likely to be high risk, leading to severe prognosis and death, regardless of age [23,24]. Mutagenesis2, .B2i.nMdiuntgagAefnfiensiist,yBainnddiInngteArffaficniaitlyCaonndtaIcnttePrrfaecdiiacltiCoonnstact Predictions VppiGsduoo14eblp66nys0u2ttmAMrDilfiaao/pttereivGdropaebnh4vr6in6iii3[aso2d2mnpuS1itnsu]s.hDgtGugitshsrialaN.t4NnaeoutvTc6tieuAVdaiev2hTvopAryD1eeMnelr6psoi/ihrdde0peGoPwt[aeMehdr2luR4slynee1en6aSvbmetl]vt2iiel.xiSyeqfalSoosiaer2urNesuraimlhidep,oeasalealDunihvvn6vnfsptisae3rd4eteseiruro3mvdspltiqAdp5ohaaucusg,nwyueraCteeiSlatrliaEesnnanrh4tasniiteical6evsignlttiTs0o,deesieecTMlnsDnaeedbiM,ssnxneyePf4u;atrsld3RPthaesiemh5nctlRaSqeGle,eeitcSyuSnrpep4rS2TiSereooo6ta4n2eMidps2urab6scsmeun0sitiPaglielddivnaraReastaeyaiyln,gtnSflAirteflioptdSihymectCaono,2ierancEseptGyCratec;nroslsO4oniagittnure6ihrdteVtntised2poanaiecIntonaurleeDhaoleglpsptyglrens-uterh1trcsaliTeiel9aybuncasMiDgrirgmgbitrlobidii4gilPyotospyyeu3eynRsnd,ao5se,tSasstrtYdshosil.otSe,ntaineei2xhfnnSsTlfCpwoyEscevt4hOluioru6oanbheerdg0VnlrygeinvhiocRgsaInttDheiDprtDhgdidoapeNo-etu4nur1oahnie3eEA9dpnnpesg5suuYibroliy,oannStpv,ia4oeois6nanls0vnsewRe.s for differential susceptibility to SARS-CoV-2; we selected all residues involved in the substrate binding for further analysis in this study. The wildtype (WT) and polymorphic variants of TMPRSS2 were analyzed, and their ∆G, KD and surface contacts were determined
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