G蛋白偶联受体，简称GPCR，在人体基因组中有800多种，负责介导超过80%的细胞信号转导。其结构或功能异常可导致重要的人类疾病，如癌症、糖尿病、神经退行性疾病、心血管疾病。受体与胞外信号分子，即配体的相互识别以及配体-受体相互作用引起的构象变化被认为是药物设计的靶点。因此，使用结构生物学手段解释配体结合受体的结构基础及相互作用机制对于开发特异性药物具有重要的意义。该项目中，申请人课题组将对GPCR家族中的人源Apelin受体展开系统的结构与功能研究，通过探索一系列配体结合受体的复合物结构，进一步了解Apelin受体与配体相互作用的机制，并基于结构设计新的配体，开发药物。目前，课题进展顺利，已成功获得Apelin受体与一个配体的高分辨率晶体。由于Apelin受体是重要的心血管疾病尤其是心脏衰竭的药物靶点，并作为HIV病毒浸染人体的共受体，针对其展开的特异性药物分子设计将具有广阔的应用前景。

G-protein coupled receptors (GPCRs) constitute the largest membrane protein family in the human genome. With over 800 family members identified so far, these receptors mediate over 80% cell signaling, ranging from photons, smells, tastes, hormones, neuropeptides, proteins, and so on. Distributed almost everywhere in the human body, GPCRs are associated with a variety of physiological and pathological processes. Dysregulation of GPCRs could lead to numerous human diseases, including cancer, immune diseases, diabetes, neurodegeneration, cardiovascular disorder, and so on. The molecular recognition of ligand in the receptor—the ligand binding mode is considered the major target for drug design. Hence, structural determination of the ligand binding pocket and the receptor conformation upon ligand binding is the key to understand the molecular mechanism for GPCRs and to guide new-generation rational drug discovery. Here, we propose to discover the structure-function relationship of the apelin receptor, an important target for cardiovascular diseases and key modulator in heart failure, by employing state-of-the-art membrane protein crystallography and other biochemical and biophysical techniques. The goal is to determine a series of first-in-class apelin receptor structures in complex with different ligand, including small molecule ligands as well as peptide ligands. These structures, together with functional characterizations, will draw a ligand binding landscape for apelin receptor and guide for structure-based drug discovery.