Alpha-2-巨球蛋白（简称α2M）是人血液中含量最为丰富的蛋白之一，具有多种重要的生理功能。α2M是人体内最重要的小蛋白酶广谱抑制剂，并可以和多种细胞因子（如TNFα，TGF-β）结合并调节其病理相关的细胞因子活性。因而，α2M是潜在的药物设计的重要靶点。但是，天然α2M蛋白结构高度动态且很不均一，目前尚缺少人源α2M的高分辨率结构，特别是对其动态构象变化和变构机制的研究还十分有限。本项目以冷冻电镜（Cryo-EM）三维重构为主要手段，利用其多构象结构分类解析优势，拟解析天然人源α2M蛋白发挥功能所依赖的S-α2M和F-α2M及其它形式的高分辨率结构，并以此为基础继续解析TNFα-α2M复合物的三维结构，为理解α2M广谱抑制小蛋白酶和调节细胞因子活性的机制提供有益的结构信息，并为靶点药物设计提供重要的结构基础。目前，本项目已经取得较好的预研结果，并提出了α2M结构变化机制的初步猜想。

Human Alpha-2-macroglobulin （α2M）is one of the most abundunt proteins in human blood and play various critical roles in physiological processes. α2M is primarily known by its ability to inhibit and clear the excess proteinases circulated in human body. It is also known to bind many important cytokines, including TNFα、TGF-β etc., and regulate their biological activities involved in pathophysiology. Therefore, α2M is potentially a great target of drug design. However, no high resolution three-dimensional structure of human α2M has been resolved due to it’s highly dynamic characteristics. Particularly, little is known on the dynamic changing process of α2M among its multi-conformations, which leads to poor understanding on the mechanism of α2M biological functions. In this project, we try to resolve the high resolution three dimensional structures of S-α2M and F-α2M, which are the two main forms adopted byα2M involved in diversified functions, taking advantage of the strong ability of Cryo-EM to differentiate multiple conformations in the same dynamic proteins. The structure of TNFα-α2M complex will be further identified based on the structural work of S-α2M and F-α2M. Taken together, the study in this project is mainly focus on the three dimensional reconstruction of multiple conformations of human native α2M which will significantly improve our knowledge of how α2M functions as poteinases inhibitor and meanwhile regulates the diseases-related cytokines. It will also provide critical structural information to drug design. Currently, we have made promising preliminary progresses on the proposed project..A hypothesis about the molecular mechanism of α2M conformational change is proposed based on our preliminary work.