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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 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.

SUBMITTER: Bezerra GA 

PROVIDER: S-EPMC5460201 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Bacterial protease uses distinct thermodynamic signatures for substrate recognition.

Bezerra Gustavo Arruda GA   Ohara-Nemoto Yuko Y   Cornaciu Irina I   Fedosyuk Sofiya S   Hoffmann Guillaume G   Round Adam A   Márquez José A JA   Nemoto Takayuki K TK   Djinović-Carugo Kristina K  

Scientific reports 20170606 1


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 m  ...[more]

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