A unique peptide-based pharmacophore identifies an inhibitory compound against the A-subunit of Shiga toxin
Abstract Shiga toxin (Stx), a major virulence factor of enterohemorrhagic Escherichia coli (EHEC), can cause fatal systemic complications. Recently, we identified a potent inhibitory peptide that binds to the catalytic A-subunit of Stx. Here, using biochemical structural analysis and X-ray crystallo...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-07-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-15316-1 |
| _version_ | 1818158132759625728 |
|---|---|
| author | Miho Watanabe-Takahashi Miki Senda Ryunosuke Yoshino Masahiro Hibino Shinichiro Hama Tohru Terada Kentaro Shimizu Toshiya Senda Kiyotaka Nishikawa |
| author_facet | Miho Watanabe-Takahashi Miki Senda Ryunosuke Yoshino Masahiro Hibino Shinichiro Hama Tohru Terada Kentaro Shimizu Toshiya Senda Kiyotaka Nishikawa |
| author_sort | Miho Watanabe-Takahashi |
| collection | DOAJ |
| description | Abstract Shiga toxin (Stx), a major virulence factor of enterohemorrhagic Escherichia coli (EHEC), can cause fatal systemic complications. Recently, we identified a potent inhibitory peptide that binds to the catalytic A-subunit of Stx. Here, using biochemical structural analysis and X-ray crystallography, we determined a minimal essential peptide motif that occupies the catalytic cavity and is required for binding to the A-subunit of Stx2a, a highly virulent Stx subtype. Molecular dynamics simulations also identified the same motif and allowed determination of a unique pharmacophore for A-subunit binding. Notably, a series of synthetic peptides containing the motif efficiently inhibit Stx2a. In addition, pharmacophore screening and subsequent docking simulations ultimately identified nine Stx2a-interacting molecules out of a chemical compound database consisting of over 7,400,000 molecules. Critically, one of these molecules markedly inhibits Stx2a both in vitro and in vivo, clearly demonstrating the significance of the pharmacophore for identifying therapeutic agents against EHEC infection. |
| first_indexed | 2024-12-11T15:25:14Z |
| format | Article |
| id | doaj.art-c2782278432e409e8b97ae9a82df8762 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-11T15:25:14Z |
| publishDate | 2022-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-c2782278432e409e8b97ae9a82df87622022-12-22T01:00:14ZengNature PortfolioScientific Reports2045-23222022-07-0112111310.1038/s41598-022-15316-1A unique peptide-based pharmacophore identifies an inhibitory compound against the A-subunit of Shiga toxinMiho Watanabe-Takahashi0Miki Senda1Ryunosuke Yoshino2Masahiro Hibino3Shinichiro Hama4Tohru Terada5Kentaro Shimizu6Toshiya Senda7Kiyotaka Nishikawa8Department of Molecular Life Sciences, Graduate School of Life and Medical Sciences, Doshisha UniversityStructural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK)Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of TokyoDepartment of Molecular Life Sciences, Graduate School of Life and Medical Sciences, Doshisha UniversityDepartment of Molecular Life Sciences, Graduate School of Life and Medical Sciences, Doshisha UniversityDepartment of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of TokyoDepartment of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of TokyoStructural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK)Department of Molecular Life Sciences, Graduate School of Life and Medical Sciences, Doshisha UniversityAbstract Shiga toxin (Stx), a major virulence factor of enterohemorrhagic Escherichia coli (EHEC), can cause fatal systemic complications. Recently, we identified a potent inhibitory peptide that binds to the catalytic A-subunit of Stx. Here, using biochemical structural analysis and X-ray crystallography, we determined a minimal essential peptide motif that occupies the catalytic cavity and is required for binding to the A-subunit of Stx2a, a highly virulent Stx subtype. Molecular dynamics simulations also identified the same motif and allowed determination of a unique pharmacophore for A-subunit binding. Notably, a series of synthetic peptides containing the motif efficiently inhibit Stx2a. In addition, pharmacophore screening and subsequent docking simulations ultimately identified nine Stx2a-interacting molecules out of a chemical compound database consisting of over 7,400,000 molecules. Critically, one of these molecules markedly inhibits Stx2a both in vitro and in vivo, clearly demonstrating the significance of the pharmacophore for identifying therapeutic agents against EHEC infection.https://doi.org/10.1038/s41598-022-15316-1 |
| spellingShingle | Miho Watanabe-Takahashi Miki Senda Ryunosuke Yoshino Masahiro Hibino Shinichiro Hama Tohru Terada Kentaro Shimizu Toshiya Senda Kiyotaka Nishikawa A unique peptide-based pharmacophore identifies an inhibitory compound against the A-subunit of Shiga toxin Scientific Reports |
| title | A unique peptide-based pharmacophore identifies an inhibitory compound against the A-subunit of Shiga toxin |
| title_full | A unique peptide-based pharmacophore identifies an inhibitory compound against the A-subunit of Shiga toxin |
| title_fullStr | A unique peptide-based pharmacophore identifies an inhibitory compound against the A-subunit of Shiga toxin |
| title_full_unstemmed | A unique peptide-based pharmacophore identifies an inhibitory compound against the A-subunit of Shiga toxin |
| title_short | A unique peptide-based pharmacophore identifies an inhibitory compound against the A-subunit of Shiga toxin |
| title_sort | unique peptide based pharmacophore identifies an inhibitory compound against the a subunit of shiga toxin |
| url | https://doi.org/10.1038/s41598-022-15316-1 |
| work_keys_str_mv | AT mihowatanabetakahashi auniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT mikisenda auniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT ryunosukeyoshino auniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT masahirohibino auniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT shinichirohama auniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT tohruterada auniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT kentaroshimizu auniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT toshiyasenda auniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT kiyotakanishikawa auniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT mihowatanabetakahashi uniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT mikisenda uniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT ryunosukeyoshino uniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT masahirohibino uniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT shinichirohama uniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT tohruterada uniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT kentaroshimizu uniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT toshiyasenda uniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin AT kiyotakanishikawa uniquepeptidebasedpharmacophoreidentifiesaninhibitorycompoundagainsttheasubunitofshigatoxin |