X连锁α地中海贫血/智能发育迟滞蛋白（ATRX）是一个大小约为2500残基的表观遗传调控因子，具有重要的异染色质靶向的染色质重塑及转录调控等功能。近年来人们发现ATRX不仅是人类先天性遗传病ATRX综合征的关键病因蛋白，而且在X染色质抑活、干细胞多能性维持与分化，病毒感染和潜伏，以及癌症发生等过程中起着重要作用。目前ATRX及其相关复合物的结构生物学研究仍十分欠缺。本项目计划以蛋白质晶体学为主要手段，与各种生物化学及细胞生物学功能分析相结合，开展ATRX蛋白自身，及其与组蛋白、染色质调控蛋白、和串联重复核酸序列等复合物的结构与功能研究。我们期望通过本研究，在分子水平上阐明ATRX在发育、干细胞、病毒感染、癌症以及ATRX综合征等正常或病理过程发挥作用的机制， 并为ATRX靶向的小分子药物的开发奠定坚实基础。

Alpha Thalassemia/Mental Retardation, X-linked (ATRX) is an important epigenetic regulator of ~2500 residues in size,characteristic of chromatin remodelling and transcriptional control at heterochromatic regions. ATRX is the key etiologic factor for ATR-X syndrome, a human congenital disease whose clinical manifestations are alpha-thalassemia and mental retardation. In addition, recent studies showed that ATRX plays critical roles in many cellular processes or diseases, including X-chromosome inactivation, stem cell pluripotency and differentiation, viral infection and latency, as well as cancer genesis and progression. To date,the structural basis for ATRX function remains largely unexplored. In this project, we plan to apply X-ray crystallography, in combination with other biochemical or cellular functional assays, to study the structure and function of ATRX and its complex with binding partners such as histones, non-histone chromatin regulators and DNA/RNA tandem repeats. We anticipate that our work shall provide critical molecular insights into ATRX function in development, stell cell, viral infection, cancer and ATR-X syndrome. This work will also pave the way for developing new smalll molecular compounds for therapeutic intervention of human diseases involving ATRX dysfunction.