Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of G_i1-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of G_i1-bound SSTR4 in complex with SST-14 and a small-molecule agonist J-2156, respectively. By comparison of the SSTR structures in different states, molecular mechanisms of agonism and antagonism were illustrated. Together with computational and functional analyses, the key determinants responsible for ligand recognition and selectivity of different SSTR subtypes and multiform binding modes of peptide and non-peptide ligands were identified. Insights gained in this study will help uncover ligand selectivity of various SSTRs and accelerate the development of new molecules with better efficacy by targeting SSTRs.

生长抑素受体（SSTRs）在抑制多种激素如生长激素和促甲状腺激素的分泌方面发挥着多种作用，因此被认为是治疗多种肿瘤的靶点。尽管针对这种多样化受体家族的治疗开发取得了很大进展，但靶向 SSTR 的药物仍然显示出有限的疗效，具有优先的结合亲和力和明显的副作用。_{在这里，我们报告了五种不同状态的 SSTR2 和 SSTR4 结构，包括分别与选择性肽拮抗剂和非肽激动剂复合的两种 SSTR2 晶体结构，以及 G i1}的低温电子显微镜 (cryo-EM) 结构-在存在内源性配体 SST-14 的情况下结合 SSTR2，以及 G _{i1的两个低温 EM 结构}-结合的 SSTR4 分别与 SST-14 和小分子激动剂 J-2156 复合。通过比较不同状态下的SSTR结构，阐明了激动和拮抗的分子机制。连同计算和功能分析，确定了负责不同 SSTR 亚型的配体识别和选择性以及肽和非肽配体的多种结合模式的关键决定因素。本研究中获得的见解将有助于揭示各种 SSTR 的配体选择性，并通过靶向 SSTR 加速开发具有更好功效的新分子。