Structural Studies of Protein-Carbohydrate Interactions

抗体对外来分子（称为抗原）的识别是免疫的一个关键方面，但令人惊讶的是，人们对结合的分子机制知之甚少。 有趣的是，免疫系统以不同的方式处理不同类型的分子。 例如，当一个携带抗体的细胞（称为B细胞）遇到一种蛋白质抗原时，它可以将其切成碎片并呈递给T细胞。 如果T细胞也将蛋白质识别为外来物，它可以刺激B细胞产生大量高度特异性的紧密结合抗体。 然而，当B细胞与碳水化合物结合时，T细胞几乎从不以这种方式提供帮助。 这项研究的重点是试图在分子水平上了解抗体如何结合碳水化合物。 我们的目标是：（1）确定免疫系统是否进化为快速识别碳水化合物抗原，以弥补缺乏T细胞的帮助。（2）阐明“交叉反应性”的基础，即抗体与化学相似的抗原（在我们的情况下是碳水化合物）结合。 (3)我们知道有一些对碳水化合物有特异性的抗体，它们也能结合“模拟”碳水化合物的蛋白质或DNA，所以我们的目标是确定这种“多特异性”的分子机制。（4）获得分子证据，证明通过改变它们的形状，单个抗体可以特异性地针对完全不同的抗原。 我们与世界各地的科学团体合作，他们已经生产了针对各种重要碳水化合物抗原（通常来自细菌）的抗体，并仔细测量了结合强度并确定了所有抗体的特异性。 我们的研究方法是通过自身产生高质量的抗体晶体，并与碳水化合物结合。 然后，我们使用一种称为“x射线晶体学”的技术，通过测量晶体如何吸收x射线来成像分子的结构，因此我们可以确切地看到抗体如何结合其抗原。 这项研究已经扩展了对抗体结合的了解，并有望为一些结合理论提供戏剧性的证据。

The recognition by antibodies of foreign molecules (called antigens) is a key aspect of immunity, but surprisingly little is known about the molecular mechanisms of binding. Interestingly, the immune system treats different kinds of molecules in different ways. For example, when an antibody-bearing cell (called a B-cell) encounters a protein antigen it can chop it into bits to present to T-cells. If a T-cell also recognizes the protein as foreign, it can stimulate B-cells into producing vast quantities of highly-specific tightly-binding antibodies. However, T-cells almost never help this way when a B-cell binds a carbohydrate. This research is focussed on trying to understand at a molecular level how antibodies bind carbohydrates. We have the objectives (1) To determine if the immune system evolved to recognize carbohydrate antigens quickly to make up for the lack of T-cell 'help.' (2) To elucidate the basis for 'cross-reactivity,' where an antibody binds to antigens (in our case carbohydrates) that are chemically similar. (3) We know that there are antibodies specific for carbohydrates that also bind proteins or DNA that 'mimic' carbohydrates, so we aim to determine the molecular mechanism for this 'polyspecificity.' (4) To obtain molecular evidence that by shifting their shapes a single antibody can be specific for completely different antigens. We work in collaboration with scientific groups around the world who have produced antibodies to various important carbohydrate antigens (usually from bacteria) and who have carefully measured the strength of binding and determined the specificities of all of their antibodies. Our investigative method is to generate high-quality crystals of the antibodies by themselves and bound to the carbohydrates. We then use a technique called 'x-ray crystallography' to image the structures of the molecules by measuring how the crystals diffract x-rays, so we can actually see exactly how the antibodies bind their antigens. This research has already expanded what is known about antibody binding, and has the promise of providing dramatic proof of some theories of binding.