Structural insights into ligand recognition and selectivity of somatostatin receptors.
Structural insights into ligand recognition and selectivity of somatostatin receptors.
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生长抑素受体的配体识别和选择性的结构见解
DOI：
10.1038/s41422-022-00679-x
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发表时间：
2022-08
期刊：
影响因子：
44.1
通讯作者：
Zhao, Qiang
中科院分区：
文献类型：
--
作者：
Zhao, Wenli;Han, Shuo;Qiu, Na;Feng, Wenbo;Lu, Mengjie;Zhang, Wenru;Wang, Mu;Zhou, Qingtong;Chen, Shutian;Xu, Wei;Du, Juan;Chu, Xiaojing;Yi, Cuiying;Dai, Antao;Hu, Liaoyuan;Shen, Michelle Y.;Sun, Yaping;Zhang, Qing;Ma, Yingli;Zhong, Wenge;Yang, Dehua;Wang, Ming-Wei;Wu, Beili;Zhao, Qiang
生长抑素受体(SSTR)在抑制生长激素、促甲状腺激素等多种激素的分泌方面发挥着广泛的作用，因此被认为是治疗多种肿瘤的靶点。尽管针对这一不同受体家族的治疗开发取得了很大进展，但针对SSTR的药物仍然显示出有限的疗效，具有较好的结合亲和力和明显的副作用。在这里，我们报道了SSTR2和SSTR4在不同状态下的五种结构，包括SSTR2分别与选择性多肽拮抗剂和非肽激动剂形成的络合物中的两种晶体结构，在内源配体SST-14存在下与Gi1结合的SSTR2的冷冻电子显微镜(Cryo-EM)结构，以及分别与SST-14和小分子激动剂J-2156形成的与Gi1结合的SSTR4的两种冷冻-EM结构。通过比较不同状态下的SSTR结构，阐明了激动型和拮抗型的分子机制。结合计算和功能分析，确定了决定不同SSTR亚型和多肽和非肽配体多种结合模式的配体识别和选择性的关键决定因素。本研究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来加速开发具有更好疗效的新分子。
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 Gi1-bound SSTR2 in the presence of the endogenous ligand SST-14, as well as two cryo-EM structures of Gi1-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.
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DOI：
10.1124/jpet.104.075531
发表时间：
2005-01-01
影响因子：
3.5
作者：
Engström, M;Tomperi, J;Wurster, S
通讯作者：
Wurster, S
影响因子：
7.3
作者：
Grace, CRR;Koerber, SC;Riek, R
通讯作者：
Riek, R
影响因子：
5.5
作者：
Hess, Berk
通讯作者：
Hess, Berk
影响因子：
64.8
作者：
Huang W;Manglik A;Venkatakrishnan AJ;Laeremans T;Feinberg EN;Sanborn AL;Kato HE;Livingston KE;Thorsen TS;Kling RC;Granier S;Gmeiner P;Husbands SM;Traynor JR;Weis WI;Steyaert J;Dror RO;Kobilka BK
通讯作者：
Kobilka BK
影响因子：
2.9
作者：
AOKI, KM;YONEZAWA, F
通讯作者：
YONEZAWA, F