Bacterial protease uses distinct thermodynamic signatures for substrate recognition.
Porphyromonas gingivalis and Porphyromonas endodontalis are important bacteria related to periodontitis, the most common chronic inflammatory disease in humans worldwide. Its comorbidity with systemic diseases, such as type 2 diabetes, oral cancers and cardiovascular diseases, continues to generate...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Nature Publishing Group
2017
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| _version_ | 1797098997403353088 |
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| author | Bezerra, G Ohara-Nemoto, Y Cornaciu, I Fedosyuk, S Hoffmann, G Round, A Márquez, J Nemoto, T Djinović-Carugo, K |
| author_facet | Bezerra, G Ohara-Nemoto, Y Cornaciu, I Fedosyuk, S Hoffmann, G Round, A Márquez, J Nemoto, T Djinović-Carugo, K |
| author_sort | Bezerra, G |
| collection | OXFORD |
| description | Porphyromonas gingivalis and Porphyromonas endodontalis are important bacteria related to periodontitis, the most common chronic inflammatory disease in humans worldwide. Its comorbidity with systemic diseases, such as type 2 diabetes, oral cancers and cardiovascular diseases, continues to generate considerable interest. Surprisingly, these two microorganisms do not ferment carbohydrates; rather they use proteinaceous substrates as carbon and energy sources. However, the underlying biochemical mechanisms of their energy metabolism remain unknown. Here, we show that dipeptidyl peptidase 11 (DPP11), a central metabolic enzyme in these bacteria, undergoes a conformational change upon peptide binding to distinguish substrates from end products. It binds substrates through an entropy-driven process and end products in an enthalpy-driven fashion. We show that increase in protein conformational entropy is the main-driving force for substrate binding via the unfolding of specific regions of the enzyme ("entropy reservoirs"). The relationship between our structural and thermodynamics data yields a distinct model for protein-protein interactions where protein conformational entropy modulates the binding free-energy. Further, our findings provide a framework for the structure-based design of specific DPP11 inhibitors. |
| first_indexed | 2024-03-07T05:17:28Z |
| format | Journal article |
| id | oxford-uuid:ddb32a33-6767-497c-b226-9d49b3b28e44 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:17:28Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:ddb32a33-6767-497c-b226-9d49b3b28e442022-03-27T09:27:02ZBacterial protease uses distinct thermodynamic signatures for substrate recognition.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ddb32a33-6767-497c-b226-9d49b3b28e44EnglishSymplectic Elements at OxfordNature Publishing Group2017Bezerra, GOhara-Nemoto, YCornaciu, IFedosyuk, SHoffmann, GRound, AMárquez, JNemoto, TDjinović-Carugo, KPorphyromonas gingivalis and Porphyromonas endodontalis are important bacteria related to periodontitis, the most common chronic inflammatory disease in humans worldwide. Its comorbidity with systemic diseases, such as type 2 diabetes, oral cancers and cardiovascular diseases, continues to generate considerable interest. Surprisingly, these two microorganisms do not ferment carbohydrates; rather they use proteinaceous substrates as carbon and energy sources. However, the underlying biochemical mechanisms of their energy metabolism remain unknown. Here, we show that dipeptidyl peptidase 11 (DPP11), a central metabolic enzyme in these bacteria, undergoes a conformational change upon peptide binding to distinguish substrates from end products. It binds substrates through an entropy-driven process and end products in an enthalpy-driven fashion. We show that increase in protein conformational entropy is the main-driving force for substrate binding via the unfolding of specific regions of the enzyme ("entropy reservoirs"). The relationship between our structural and thermodynamics data yields a distinct model for protein-protein interactions where protein conformational entropy modulates the binding free-energy. Further, our findings provide a framework for the structure-based design of specific DPP11 inhibitors. |
| spellingShingle | Bezerra, G Ohara-Nemoto, Y Cornaciu, I Fedosyuk, S Hoffmann, G Round, A Márquez, J Nemoto, T Djinović-Carugo, K Bacterial protease uses distinct thermodynamic signatures for substrate recognition. |
| title | Bacterial protease uses distinct thermodynamic signatures for substrate recognition. |
| title_full | Bacterial protease uses distinct thermodynamic signatures for substrate recognition. |
| title_fullStr | Bacterial protease uses distinct thermodynamic signatures for substrate recognition. |
| title_full_unstemmed | Bacterial protease uses distinct thermodynamic signatures for substrate recognition. |
| title_short | Bacterial protease uses distinct thermodynamic signatures for substrate recognition. |
| title_sort | bacterial protease uses distinct thermodynamic signatures for substrate recognition |
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