Bacterial protease uses distinct thermodynamic signatures for substrate recognition

Abstract 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...

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Autores principales:	Gustavo Arruda Bezerra, Yuko Ohara-Nemoto, Irina Cornaciu, Sofiya Fedosyuk, Guillaume Hoffmann, Adam Round, José A. Márquez, Takayuki K. Nemoto, Kristina Djinović-Carugo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1b171c954af24de4a2b197fb3e496657
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spelling	oai:doaj.org-article:1b171c954af24de4a2b197fb3e4966572021-12-02T12:32:19ZBacterial protease uses distinct thermodynamic signatures for substrate recognition10.1038/s41598-017-03220-y2045-2322https://doaj.org/article/1b171c954af24de4a2b197fb3e4966572017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03220-yhttps://doaj.org/toc/2045-2322Abstract 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.Gustavo Arruda BezerraYuko Ohara-NemotoIrina CornaciuSofiya FedosyukGuillaume HoffmannAdam RoundJosé A. MárquezTakayuki K. NemotoKristina Djinović-CarugoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gustavo Arruda Bezerra Yuko Ohara-Nemoto Irina Cornaciu Sofiya Fedosyuk Guillaume Hoffmann Adam Round José A. Márquez Takayuki K. Nemoto Kristina Djinović-Carugo Bacterial protease uses distinct thermodynamic signatures for substrate recognition
description	Abstract 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.
format	article
author	Gustavo Arruda Bezerra Yuko Ohara-Nemoto Irina Cornaciu Sofiya Fedosyuk Guillaume Hoffmann Adam Round José A. Márquez Takayuki K. Nemoto Kristina Djinović-Carugo
author_facet	Gustavo Arruda Bezerra Yuko Ohara-Nemoto Irina Cornaciu Sofiya Fedosyuk Guillaume Hoffmann Adam Round José A. Márquez Takayuki K. Nemoto Kristina Djinović-Carugo
author_sort	Gustavo Arruda Bezerra
title	Bacterial protease uses distinct thermodynamic signatures for substrate recognition
title_short	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_sort	bacterial protease uses distinct thermodynamic signatures for substrate recognition
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/1b171c954af24de4a2b197fb3e496657
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_version_	1718394081568096256

Bacterial protease uses distinct thermodynamic signatures for substrate recognition

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