胶原蛋白是人体内含量最多的蛋白质，起着维持组织和器官结构完整性的作用。它们的结构功能异常与多种疾病有关，比如组织中胶原蛋白的过量堆积会导致纤维化疾病，而胶原蛋白合成不足或者结构紊乱会引起成骨不全及骨质疏松。最新研究发现，一个既具有分子伴侣又具有修饰酶作用的脯氨酸羟化酶三元复合物（P3H1/CRTAP/CypB）参与了胶原蛋白的合成，且对胶原的正确折叠至关重要。该复合物功能的缺损会引起成骨不全症等疾病。我们最近解析了该复合物中P3H1羟化酶结构域的晶体结构，发现它具有一个相对独特的底物结合口袋。本项目将在此工作的基础上，着重研究该脯氨酸3-羟化酶复合物特异性地羟化胶原蛋白986位脯氨酸的分子机制，并尝试解析该三元复合物的三维结构，阐明该复合物调节胶原分子折叠的机制。这项研究结果将为如何调节胶原蛋白的生成提供理论依据，对设计抗组织纤维化和成骨不全等疾病的药物具有重要的指导意义.

As the most abundant protein in the human body, collagen is crucial in maintaining the structural integrity of tissue and organ. Their structural dysfunction are associated with many diseases, such as tissue fibrosis due to excessive accumulation of collagen, and osteogenesis imperfecta due to structural disorder of collagen. Recent studies have shown that a proline hydroxylase ternary complex (P3H1 / CRTAP / CypB), with chaperone function and modifying enzyme activity in collagen synthesis, is essential for proper collagen folding. Defects in this complex often lead to diseases such as osteogenesis imperfecta. We have now solved the crystal structure of the hydroxylase domain of P3H1 and found that it has a relatively unique substrate binding pocket. Based on these findings, this project will focus on the molecular mechanisms how the proline 3-hydroxylase complex specifically modifies residue Pro986 in collagen and how this ternary complex assembles in facilitating collagen folding. This will clarify how the complex modifies collagen and how it promotes collagen folding. The results of this study will shed light on how to design and select agents targeting fibrosis and osteogenesis imperfecta and other collagen related disorders.