Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia.
The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
Biochem Pharmacol. 2018 Apr;150:214-244. doi: 10.1016/j.bcp.2018.02.005. Epub 2018 Feb 16.
Class B peptide hormone GPCRs are targets for the treatment of major chronic disease. Peptide ligands of these receptors display biased agonism and this may provide future therapeutic advantage. Recent active structures of the calcitonin (CT) and glucagon-like peptide-1 (GLP-1) receptors reveal distinct engagement of peptides with extracellular loops (ECLs) 2 and 3, and mutagenesis of the GLP-1R has implicated these loops in dynamics of receptor activation. In the current study, we have mutated ECLs 2 and 3 of the human CT receptor (CTR), to interrogate receptor expression, peptide affinity and efficacy. Integration of these data with insights from the CTR and GLP-1R active structures, revealed marked diversity in mechanisms of peptide engagement and receptor activation between the CTR and GLP-1R. While the CTR ECL2 played a key role in conformational propagation linked to Gs/cAMP signalling this was mechanistically distinct from that of GLP-1R ECL2. Moreover, ECL3 was a hotspot for distinct ligand- and pathway-specific effects, and this has implications for the future design of biased agonists of class B GPCRs.
B 类肽激素 GPCR 是治疗重大慢性疾病的靶点。这些受体的肽配体显示出偏向激动作用,这可能为未来的治疗带来优势。最近的降钙素 (CT) 和胰高血糖素样肽-1 (GLP-1) 受体的活性结构揭示了肽与细胞外环 2 和 3 的不同结合,GLP-1R 的突变暗示这些环在受体激活的动力学中起作用。在本研究中,我们突变了人类 CT 受体 (CTR) 的 ECLs 2 和 3,以研究受体表达、肽亲和力和功效。将这些数据与 CTR 和 GLP-1R 活性结构的见解相结合,揭示了 CTR 和 GLP-1R 之间肽结合和受体激活的机制存在显著差异。虽然 CTR ECL2 在与 Gs/cAMP 信号传导相关的构象传播中起着关键作用,但它与 GLP-1R ECL2 的机制不同。此外,ECL3 是独特配体和途径特异性效应的热点,这对 B 类 GPCR 偏向激动剂的未来设计具有重要意义。