Bacterial protease uses distinct thermodynamic signatures for substrate recognition.
Bacterial protease uses distinct thermodynamic signatures for substrate recognition.
复制标题
DOI：
10.1038/s41598-017-03220-y
复制
发表时间：
2017-06-06
影响因子：
4.6
通讯作者：
Djinović-Carugo K
中科院分区：
文献类型：
--
作者：
Bezerra GA;Ohara-Nemoto Y;Cornaciu I;Fedosyuk S;Hoffmann G;Round A;Márquez JA;Nemoto TK;Djinović-Carugo K
牙龈卟啉单胞菌和牙髓卟啉单胞菌是与牙周炎相关的重要细菌，牙周炎是人类最常见的慢性炎症性疾病。它与系统性疾病的共病，如2型糖尿病、口腔癌症和心血管疾病，继续引起人们的极大兴趣。令人惊讶的是，这两种微生物并不发酵碳水化合物；相反，它们使用蛋白质底物作为碳源和能源。然而，它们能量代谢的潜在生化机制仍不清楚。在这里，我们发现二肽基肽酶11(DPP11)是这些细菌中的一种中心代谢酶，它在多肽结合时经历构象变化，以区分底物和最终产物。它通过熵驱动过程将基材结合在一起，并以焓驱动的方式将最终产品结合在一起。我们发现，蛋白质构象熵的增加是底物结合的主要驱动力，通过酶的特定区域的展开(“熵库”)。我们的结构和热力学数据之间的关系产生了蛋白质-蛋白质相互作用的独特模型，其中蛋白质构象熵调节结合自由能。此外，我们的发现为特定DPP11抑制剂的基于结构的设计提供了一个框架。
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.