组蛋白去乙酰酶（HDACs）是重要的表观调控因子，与癌症的发生及恶化密切相关，也是目前最有前景的抗癌药物筛选的靶点之一。组蛋白去乙酰酶多以蛋白复合物形式发挥功能，但复合物结构信息的缺失极大地限制了药物作用机制的研究以及新型ˎ安全ˎ有效ˎ有选择性抑制剂的开发。本课题组的前期研究已经建立了可以同时获取蛋白质复合物序列ˎ结构和功能信息的native top-down质谱新方法及靶向药物筛选超滤液质联用方法，本工作拟以I型HDAC多蛋白复合物为研究体系，通过整合native top-down质谱及表面标记ˎ交联ˎ限制性水解等技术建立整合结构质谱方法，以实现I型HDAC多蛋白复合物的结构解析及药物作用机制研究，并在此基础上筛选新型抑制剂。这项研究不仅可以深化我们对HDAC复合物结构的认识，也将为开发具有HDAC亚型选择性或是HDAC亚蛋白复合物选择性的抑制剂开辟新方法、新思路，推动药物研发。

Histone deacetylases (HDACs) as key epigenetic regulators play a central role in the regulation of cellular properties that related to development and progression of cancer. Targeting HDACs to develop inhibitors represents one of the most promising therapeutical approaches in anticancer therapies. Most of the current inhibitors are pan-HDAC inhibitors without HDAC isoform selectivity. The major challenge in HDAC inhibitor development is finding drugs with HDAC selectivity to improve drug efficacy and safety. However, many HDACs exist as components of multiprotein complexes, the lack of structures for multiprotein HDAC complexes and the difficulty of probing the interactions of small molecules with macromolecular protein complexes have hampered the search for HDAC inhibitors with isoform-selectivity. The goal of this research is (I) to develop an advanced structural MS approach that can deliver structural information of protein complexes in a rapid and sensitive manner, and (II) to build up the architectures of HDAC multiprotein complexes to understand how HDAC complexes assemble and function, and (III) to probe the mechanisms of action of HDAC inhibitors. To achieve these goals, I will couple an innovative native top-down MS approach that I recently developed with hydroxyl radical footprinting and cross-linking MS. The native top-down MS method not only harvests the synergy between proteomics MS and native MS, but also enlarges the yield of experimental constraints describing multiprotein complexes. The integration of complementary techniques such as surface labelling and cross-linking MS will further enhance this approach. This research will greatly increase the level of structural insights of HDAC complex topologies and pave the path for the development of HDAC inhibitors with HDAC isoform-selectivity or HDAC sub-complex specificity. More broadly, this work will advance structural biology and drug discovery.