Molecular insights into the dynamic modulation of bacterial ClpP function and oligomerization by peptidomimetic boronate compounds
Abstract Bacterial caseinolytic protease P subunit (ClpP) is important and vital for cell survival and infectivity. Recent publications describe and discuss the complex structure–function relationship of ClpP and its processive activity mediated by 14 catalytic sites. Even so, there are several aspe...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-51787-0 |
| _version_ | 1827327691612749824 |
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| author | Bruno Alves França Sven Falke Holger Rohde Christian Betzel |
| author_facet | Bruno Alves França Sven Falke Holger Rohde Christian Betzel |
| author_sort | Bruno Alves França |
| collection | DOAJ |
| description | Abstract Bacterial caseinolytic protease P subunit (ClpP) is important and vital for cell survival and infectivity. Recent publications describe and discuss the complex structure–function relationship of ClpP and its processive activity mediated by 14 catalytic sites. Even so, there are several aspects yet to be further elucidated, such as the paradoxical allosteric modulation of ClpP by peptidomimetic boronates. These compounds bind to all catalytic sites, and in specific conditions, they stimulate a dysregulated degradation of peptides and globular proteins, instead of inhibiting the enzymatic activity, as expected for serine proteases in general. Aiming to explore and explain this paradoxical effect, we solved and refined the crystal structure of native ClpP from Staphylococcus epidermidis (Se), an opportunistic pathogen involved in nosocomial infections, as well as ClpP in complex with ixazomib at 1.90 Å and 2.33 Å resolution, respectively. The interpretation of the crystal structures, in combination with complementary biochemical and biophysical data, shed light on how ixazomib affects the ClpP conformational state and activity. Moreover, SEC-SAXS and DLS measurements show, for the first time, that a peptidomimetic boronate compound also induces the assembly of the tetradecameric structure from isolated homomeric heptameric rings of a gram-positive organism. |
| first_indexed | 2024-03-07T15:05:01Z |
| format | Article |
| id | doaj.art-1dc8df3793c247a7821530fc163f0574 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-07T15:05:01Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-1dc8df3793c247a7821530fc163f05742024-03-05T18:55:44ZengNature PortfolioScientific Reports2045-23222024-01-0114111310.1038/s41598-024-51787-0Molecular insights into the dynamic modulation of bacterial ClpP function and oligomerization by peptidomimetic boronate compoundsBruno Alves França0Sven Falke1Holger Rohde2Christian Betzel3Institute of Biochemistry and Molecular Biology, Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg, c/o DESY, Build. 22aCenter for Free-Electron Laser Science CFEL, DESYInstitute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-EppendorfInstitute of Biochemistry and Molecular Biology, Laboratory for Structural Biology of Infection and Inflammation, University of Hamburg, c/o DESY, Build. 22aAbstract Bacterial caseinolytic protease P subunit (ClpP) is important and vital for cell survival and infectivity. Recent publications describe and discuss the complex structure–function relationship of ClpP and its processive activity mediated by 14 catalytic sites. Even so, there are several aspects yet to be further elucidated, such as the paradoxical allosteric modulation of ClpP by peptidomimetic boronates. These compounds bind to all catalytic sites, and in specific conditions, they stimulate a dysregulated degradation of peptides and globular proteins, instead of inhibiting the enzymatic activity, as expected for serine proteases in general. Aiming to explore and explain this paradoxical effect, we solved and refined the crystal structure of native ClpP from Staphylococcus epidermidis (Se), an opportunistic pathogen involved in nosocomial infections, as well as ClpP in complex with ixazomib at 1.90 Å and 2.33 Å resolution, respectively. The interpretation of the crystal structures, in combination with complementary biochemical and biophysical data, shed light on how ixazomib affects the ClpP conformational state and activity. Moreover, SEC-SAXS and DLS measurements show, for the first time, that a peptidomimetic boronate compound also induces the assembly of the tetradecameric structure from isolated homomeric heptameric rings of a gram-positive organism.https://doi.org/10.1038/s41598-024-51787-0 |
| spellingShingle | Bruno Alves França Sven Falke Holger Rohde Christian Betzel Molecular insights into the dynamic modulation of bacterial ClpP function and oligomerization by peptidomimetic boronate compounds Scientific Reports |
| title | Molecular insights into the dynamic modulation of bacterial ClpP function and oligomerization by peptidomimetic boronate compounds |
| title_full | Molecular insights into the dynamic modulation of bacterial ClpP function and oligomerization by peptidomimetic boronate compounds |
| title_fullStr | Molecular insights into the dynamic modulation of bacterial ClpP function and oligomerization by peptidomimetic boronate compounds |
| title_full_unstemmed | Molecular insights into the dynamic modulation of bacterial ClpP function and oligomerization by peptidomimetic boronate compounds |
| title_short | Molecular insights into the dynamic modulation of bacterial ClpP function and oligomerization by peptidomimetic boronate compounds |
| title_sort | molecular insights into the dynamic modulation of bacterial clpp function and oligomerization by peptidomimetic boronate compounds |
| url | https://doi.org/10.1038/s41598-024-51787-0 |
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