Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Cell. 2019 Oct 31;179(4):895-908.e21. doi: 10.1016/j.cell.2019.10.010.
The peptidergic system is the most abundant network of ligand-receptor-mediated signaling in humans. However, the physiological roles remain elusive for numerous peptides and more than 100 G protein-coupled receptors (GPCRs). Here we report the pairing of cognate peptides and receptors. Integrating comparative genomics across 313 species and bioinformatics on all protein sequences and structures of human class A GPCRs, we identify universal characteristics that uncover additional potential peptidergic signaling systems. Using three orthogonal biochemical assays, we pair 17 proposed endogenous ligands with five orphan GPCRs that are associated with diseases, including genetic, neoplastic, nervous and reproductive system disorders. We also identify additional peptides for nine receptors with recognized ligands and pathophysiological roles. This integrated computational and multifaceted experimental approach expands the peptide-GPCR network and opens the way for studies to elucidate the roles of these signaling systems in human physiology and disease. VIDEO ABSTRACT.
肽能系统是人类中配体-受体介导信号转导最丰富的网络。然而，对于许多肽类和超过 100 种 G 蛋白偶联受体 (GPCR)，其生理作用仍然难以捉摸。在这里，我们报告了同源肽和受体的配对。通过对 313 个物种进行比较基因组学研究，并对人类 A 类 GPCR 的所有蛋白质序列和结构进行生物信息学分析，我们确定了揭示其他潜在肽能信号系统的普遍特征。使用三种正交生化测定法，我们将 17 种拟议的内源性配体与 5 种与疾病相关的孤儿 GPCR 配对，这些疾病包括遗传、肿瘤、神经和生殖系统疾病。我们还为九个具有已知配体和病理生理作用的受体鉴定了其他肽类。这种综合的计算和多方面的实验方法扩展了肽-GPCR 网络，并为阐明这些信号系统在人类生理学和疾病中的作用的研究开辟了道路。视频摘要。
