G 蛋白偶联受体(GPCR)是人体内最大的受体蛋白质家族，介导细胞内信号转导，是极其重要的药物靶标分子，但其结构解析一直是极具挑战性的蛋白质科学难题。申请人成功解析了两种1型人免疫缺陷病毒（HIV-1)共受体——趋化因子受体CXCR4 和CCR5的晶体结构，这两种GPCR结构有助于深入理解HIV病毒感染人体细胞的分子机制，并揭示了抗HIV病毒感染药物马拉维若的变构调节机制，为新型抗艾滋病药物的研发提供了结构基础。此外，CXCR4晶体结构第一次为GPCR 二聚化的研究提供了直接结构依据。上述研究成果均发表在Science杂志上。申请人将通过解析CXCR4和CCR5与HIV糖蛋白gp120结合的复合物结构，继续深入研究HIV病毒的感染机制；同时，开展针对其它重要GPCR 蛋白的结构解析和新配体研发工作，这将有助于揭示不同种类GPCR传导细胞信号的分子机制，并为自主药物研发提供结构基础。

G protein-coupled receptors (GPCRs) comprise the largest protein family in human genome. The receptors sense molecules outside the cell and activate inside signal transduction pathways. GPCRs are involved in many human diseases, and represent the target of approximately 40% of all modern medicinal drugs. Structural studies of GPCRs remain enormously challenging. The applicant have successfully solved crystal structures of two Human Immunodeficiency Virus-1 (HIV-1) coreceptors, chemokine receptors CXCR4 and CCR5. The structures deepen our understanding of the molecular mechanisms of HIV-1 infection, and reveal the allosteric modulation mechanism of anti-HIV infection drug maraviroc. CXCR4 and CCR5 structures lay a foundation for carrying out next generation anti-HIV drug discovery. In addition, all CXCR4 structures obtained reveal a consistent homodimer, which provides evidence for GPCR dimerization studies in the first time. The above findings have been published in Science in 2010 and 2013. The applicant will continue her studies on the HIV-1 coreceptors by solving the complex structures of CXCR4 and CCR5 bound to the HIV-1 glycoprotein gp120, and perform structural studies and novel ligand discovery of other important GPCRs. These studies will deepen our understanding on the molecular mechanisms of cell signal transduction by different GPCRs, and facilitate structure-based drug discovery.

G蛋白偶联受体（G protein-coupled receptor, GPCR）是人体内最大的膜受体蛋白家族，在细胞信号转导过程中发挥关键作用，与众多人体疾病密切相关，是极其重要的药物靶标分子。GPCR的结构解析难度大，严重制约了GPCR相关的功能研究和药物研发。本项目针对与心血管疾病和糖尿病等人体重大疾病相关的多种GPCR开展结构生物学研究，成功解析了嘌呤能受体P2Y1R、胰高血糖素受体GCGR和神经肽Y受体NPY1R等重要GPCR蛋白的三维结构，阐明了不同种类GPCR与配体的特异性结合模式，有助于深入理解GPCR对细胞信号的识别、转导和调控机制，并为相关药物研发提供了重要的结构基础。此外，针对艾滋病毒共受体CCR5与艾滋病毒糖蛋白gp120结合的复合物进行蛋白表达和纯化，获得了高质量的蛋白样品，为后续的结构研究和艾滋病毒感染机制的研究打下了坚实的基础。项目相关研究成果在国际顶级学术期刊Nature发表3篇研究论文。