Structural Modeling of the TMPRSS Subfamily of Host Cell Proteases Reveals Potential Binding Sites

Abstract

The transmembrane protease serine subfamily (TMPRSS) has at least eight members with known protein sequence: TMPRSS2, TMPRRS3, TMPRSS4, TMPRSS5, TMPRSS6, TMPRSS7, TMPRSS9, TMPRSS11, TMPRSS12 and TMPRSS13. A majority of these TMPRSS proteins have key roles in human hemostasis as well as promoting certain pathologies, including several types of cancer. In addition, TMPRSS proteins have been shown to facilitate the entrance of respiratory viruses into human cells, most notably TMPRSS2 and TMPRSS4 activate the spike protein of the SARS-CoV-2 virus. Despite the wide range of functions that these proteins have in the human body, none of them have been successfully crystallized. The lack of structural data has significantly hindered any efforts to identify potential drug candidates with high selectivity to these proteins. In this study, we present homology models for all members of the TMPRSS family including any known isoform (the homology model of TMPRSS2 is not included in this study as it has been previously published). The atomic coordinates for all homology models have been refined and equilibrated through molecular dynamic simulations. The structural data revealed potential binding sites for all TMPRSS as well as key amino acids that can be targeted for drug selectivity.