胰高血糖素样肽-1受体(GLP1R)的结构生物学研究

Type 2 diabetes is a rising global health problem and it attracts extensive attention for new treatments. The incretin peptide, GLP-1, is currently a major target for the development of therapeutics in type 2 diabetes. Although GLP-1 functions thought a class B G-protein-coupled receptor, GLP-1R (glucagon-like peptide-1 receptor), we know little about its structure and signaling mechanism. The GLP-1R contains a N-terminal ~120-residue extracellular domain (ECD) followed by a transmembrane domain (TMD). Current two-step binding model suggests that the GLP-1 binds to the ECD first through its C-terminal helix, which then facilitates the docking of the N-terminal fragment to the pocket of the TMD. However, without a three-dimensional structure, diabetic researchers have, in essence, been operating “ in the dark”. We are attempting to solve the structure of GLP-1R complexes with its peptide ligands as well as small molecule compounds. We have successfully expressed the full length or fragments of GLP-1R in insect cells. Crystallizing effort is currently underway. Our study will not only shed lights on how the GLP-1R transmits signals from extracellular molecules including GLP-1 to intracellular adaptors, but also provide guidance on designing of next generation drugs for treatment of type 2 diabetes.

2型糖尿病正逐渐成为人类健康的重大威胁。 肠降血糖素肽GLP-1是目前研发治疗2型糖尿病的一个主要靶标。GLP-1的功能是通过结合 胰高血糖素样肽-1受体(GLP1R， B家族GPCR的一种)而实施，人们目前对该受体的结构和信号通路知之甚少。GLP-1R包含一个N-末端约120个残基的胞外结构域(ECD)和一个跨膜结构域(TMD)。目前学界公认的结合模式是，GLP-1通过其C-末端的螺旋区结合到受体的ECD，然后N-末端片段锚定到TMD的口袋中从而激活受体。然而由于三维结构的缺乏，这个激活模型缺乏直接的实验证据。本课题试图解析GLP-1R与小分子或多肽配体的复合物结构。我们在昆虫细胞中已成功表达出GLP-1R的片段和全长蛋白，目前正在努力获得具有衍射能力的晶体。本研究将不仅有助于阐明GLP-1R如何将信号从胞外传递到胞内，同时， 还将为治疗2型糖尿病提供药物设计方面的指导。

2型糖尿病正逐渐成为人类健康的重大威胁 。 GLP-1R（胰高血糖素样肽-1受体）是目前研发治疗2型糖尿病的一个热门靶标， 但缺乏口服小分子药物。GLP-1通过结合并激活GLP-1R 继而引起胰岛素的合成和分泌从而控制血糖，而我们目前对该受体的结构和信号通路知之甚少。我们首次获得了受体结合小分子别构抑制剂的复合物晶体结构，分辨率达到2.7埃，该结构揭示出小分子的独特结合方式。我们同时构建了一个别构激活剂的结合模型，并得到了实验数据的支持。这项研究工作不仅阐明了B型GPCR精细的别构调节方式, 更为靶向GLP-1R的口服小分子药物研发提供了重要线索。