Structural basis for activation of somatostatin receptor 5 by cyclic neuropeptide agonists

• 成果类型: Article
• 署名作者: Li, Jingru; You, Chongzhao; Li, Yang; Li, Changyao; Fan, Wenjia; Chen, Zecai; Hu, Wen; Wu, Kai; Xu, H. Eric; Zhao, Li-Hua
• 署名单位: Nanjing University of Chinese Medicine; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Lingang Laboratory; ShanghaiTech University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13038
• DOI: 10.1073/pnas.2321710121
• 发表日期: 2024-06-25
• 关键词: smooth-muscle-cells; molecular pharmacology; expression; analog; proliferation; Visualization; secretion; subtypes; biology; SYSTEM

摘要

Somatostatin receptor 5 (SSTR5) is an important G protein-coupled receptor and drug target for neuroendocrine tumors and pituitary disorders. This study presents two high- resolution cryogenicelectron microscope structures of the SSTR5-Gi complexes bound to the cyclic neuropeptide agonists, cortistatin-17 (CST17) and octreotide, with resolutions of 2.7 & Aring; and 2.9 & Aring;, respectively. The structures reveal that binding of these peptides causes rearrangement of a hydrophobic lock, consisting of residues from transmembrane helices TM3 and TM6. This rearrangement triggers outward movement of TM6, enabling G alpha i protein engagement and receptor activation. In addition to hydrophobic interactions, CST17 forms conserved polar contacts similar to somatostatin-14 binding to SSTR2, while further structural and functional analysis shows that extracellular loops differently recognize CST17 and octreotide. These insights elucidate agonist selectivity and activation mechanisms of SSTR5, providing valuable guidance for structure - based drug development targeting this therapeutically relevant receptor.