Structural basis for nutrient acquisition by dominant members of the gut microbiota

大肠是由一个极其密集的细菌群体定植的，统称为结肠微生物群。最近的研究表明，微生物群在维持正常的健康和营养方面发挥着重要作用。微生物群失衡与多种疾病有关，从自身免疫性疾病到癌症和肥胖。微生物群的功能和组成取决于个体微生物在人类大肠的高度竞争环境中获取淀粉和其他膳食多糖等营养物质的能力。这一营养获取过程是由嵌入细菌细胞包膜的蛋白质机器进行的。在许多微生物群成员中，这个机器是一个由底物结合蛋白（称为SusD）和通道形成转运蛋白（称为SusC）组成的双组分复合物。我们用x射线晶体学测定了一个SusCD配合物的第一个三维原子结构，并获得了另一个SusCD配合物的高质量晶体。这些令人兴奋的初步数据构成了本提案的基础，我们将详细阐明这些SusCD复合物如何将其底物运输到细菌细胞中。通过回答一些“它是如何发生的？”的问题，我们的项目将为微生物群的功能提供基本的见解，并理解人类微生物群的共生关系。重要的是，这些结果将是对目前大多数微生物群研究的及时和必要的补充，这些研究的重点是回答诸如“谁在那里，什么时候？”之类的问题。通过将机制生物学和系统生物学联系起来，我们的项目还可以通过干扰关键的营养吸收过程来操纵微生物群的组成，从而提供实际意义。

The large bowel is colonised by an extremely dense population of bacteria, collectively termed the colonic microbiota. Recent research indicates that the microbiota play an important role in maintaining normal health and nutrition. Imbalances in the microbiota have been linked to a wide range of diseases from autoimmune disease to cancer and obesity. The function and composition of the microbiota is dependent on the ability of individual micro-organisms to acquire nutrients such as starch and other dietary polysaccharides in the highly competitive environment of the human large bowel. This process of nutrient acquisition is carried out by protein machines embedded in the bacterial cell envelope. In many microbiota members, this machine is a two-component complex consisting of a substrate binding protein (termed SusD) and a channel-forming transport protein (termed SusC). We have determined the first three-dimensional atomic structure of a SusCD complex by X-ray crystallography and have obtained good-quality crystals for another SusCD complex. These exciting preliminary data form the basis of this proposal, in which we will elucidate in detail how these SusCD complexes transport their substrates into the bacterial cell. By answering a number of "how does it happen?" questions, our project will provide fundamental insights into the functioning of the microbiota and understanding the human-microbiota symbiosis. Importantly, such results will be a timely and necessary complement to most current microbiota research, which is focused on answering questions such as "who is there and when?". By linking mechanistic and systems biology, our project could also have practical implications by providing insights to manipulate the composition of the microbiota via interference with critical nutrient uptake processes.