Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators
Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators
复制标题
与变构调节剂复合的人 GLP-1 受体跨膜结构域结构。
DOI：
10.1038/nature22378
复制
发表时间：
2017-06-08
期刊：
影响因子：
64.8
通讯作者：
Stevens, Raymond C.
中科院分区：
文献类型：
--
作者：
Song, Gaojie;Yang, Dehua;Stevens, Raymond C.
胰高血糖素样肽-1受体（GLP-1R）和胰高血糖素受体（GCGR）是g蛋白偶联受体（gpcr）分泌素样B类家族的成员，在胰岛素释放和葡萄糖稳态中具有相反的生理作用(1)。2型糖尿病的治疗需要GLP-1R的正向调节来抑制胰高血糖素的分泌，并以葡萄糖依赖的方式刺激胰岛素的分泌(2)。在这里，我们报道了人类GLP-1R跨膜结构域与两种不同的负变构调节剂PF-06372222和NNC0640在2.7和3.0埃分辨率下的晶体结构。这些结构揭示了GLP-1R和GCGR中存在的负变构调节剂的共同结合袋(3)，位于V-VII螺旋外，靠近受体的细胞内一半。该受体与限制螺旋VI细胞内尖端运动的化合物呈非活性构象，这种运动通常与a类gpcr的激活机制有关（4-6）。分子模拟和诱变研究表明，激动剂阳性变构调节剂靶向相同的一般区域，但在螺旋V和VI之间的界面上有一个不同的子口袋，这可能促进细胞内结合位点的形成，增强g蛋白偶联。
The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis(1). The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner(2). Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 angstrom resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR(3) and located outside helices V-VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs(4-6). Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.