Drugs that promote the association of protein complexes are an emerging therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR) ligand that stabilizes an active state conformation by cooperatively binding both the receptor and orthosteric ligand, thereby acting as a ‘molecular glue’. LSN3160440 is a positive allosteric modulator of the GLP-1R optimized to increase the affinity and efficacy of GLP-1(9-36), a proteolytic product of GLP-1(7-36). The compound enhances insulin secretion in a glucose-, ligand- and GLP-1R-dependent manner. Cryo-electron microscopy determined the structure of the GLP-1R bound to LSN3160440 in complex with GLP-1 and heterotrimeric G_s. The modulator binds high in the helical bundle at an interface between TM1 and TM2, allowing access to the peptide ligand. Pharmacological characterization showed strong probe dependence of LSN3160440 for GLP-1(9-36) versus oxyntomodulin that is driven by a single residue. Our findings expand protein–protein modulation drug discovery to uncompetitive, active state stabilizers for peptide hormone receptors.

促进蛋白质复合物缔合的药物是一种新兴的治疗策略。我们报告发现一种G蛋白偶联受体（GPCR）配体的发现，该配体通过与受体和正构配体协同结合来稳定活性状态构象，从而充当“分子胶”。LSN3160440是GLP-1R的正变构调节剂，经过优化可提高GLP-1（9-36）（GLP-1（7-36）的蛋白水解产物）的亲和力和功效。该化合物以葡萄糖，配体和GLP-1R依赖性方式增强胰岛素分泌。低温电子显微镜确定的GLP-1R的结构结合到LSN3160440在复杂的GLP-1和异源三聚G ^_小号。调节剂在TM1和TM2之间的界面处的螺旋束中高结合，从而允许接近肽配体。药理学表征显示LSN3160440对GLP-1（9-36）的探针依赖性强于由单个残基驱动的胃泌酸调节素。我们的发现将蛋白质-蛋白质调节药物的发现扩展到了肽激素受体的非竞争性，活性状态稳定剂。