Structural basis of peptidomimetic agonism revealed by small- molecule GLP-1R agonists Boc5 and WB4-24.
Structural basis of peptidomimetic agonism revealed by small- molecule GLP-1R agonists Boc5 and WB4-24.
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小分子 GLP-1R 激动剂 Boc5 和 WB4-24 揭示的拟肽激动作用的结构基础
DOI：
10.1073/pnas.2200155119
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发表时间：
2022-05-17
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
胰高血糖素样肽-1受体（GLP-1R）激动剂对治疗2型糖尿病和肥胖有效。虽然大多数临床使用的药物需要皮下注射，但Boc5作为GLP-1R的第一种正位非肽类激动剂，其口服生物利用度较差，阻碍了其治疗发展。Boc5及其密切相关的类似物WB4-24的低温电镜结构显示，非肽类GLP-1R激动剂的结合口袋位于跨膜结构域更深的地方。与该位点的分子相互作用可能促进广泛的体内激动活性，除了可能负责偏倚信号传导的上部螺旋束。这些发现加深了我们对GLP-1R的拟肽激动作用的理解，并可能有助于设计针对这一重要靶点的更好的药物先导。胰高血糖素样肽-1受体（GLP-1R）激动剂对治疗2型糖尿病和肥胖有效，并证实对心血管有益。然而，大多数激动剂都是多肽，需要皮下注射，除了口服的semaglutide。Boc5被确定为GLP-1R的第一个正构非肽激动剂，在体外和体内模拟GLP-1的广泛生物活性。在这里，我们报道了Boc5及其类似物WB4-24与人类GLP-1R和Gs蛋白复合物的低温电镜结构。结合胞外结构域、胞外环2和跨膜（TM）螺旋1、2、3和7，这两种化合物的一个臂深深地插入到通常由肽激动剂可进入的正构结合袋的底部，从而与GLP-1中的A8至D15残基部分重叠。与此同时，另外三个臂延伸到TM1-TM7、TM1-TM2和TM2-TM3间隙，显示出与先前已知的小分子激动剂LY3502970基本相似的相互作用特征。这种独特的结合模式创造了一种独特的构象，赋予GLP-1R非肽调节剂诱导的拟肽激动作用和偏倚信号。此外，Boc5和WB4-24这两个紧密相关的化合物之间的构象差异，为未来开发靶向GLP-1R的小分子药物提供了一个微调药理功效的结构框架。
Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious in the treatment of type 2 diabetes and obesity. While most clinically used agents require subcutaneous injection, Boc5, as the first orthosteric nonpeptidic agonist of GLP-1R, suffers from poor oral bioavailability that hinders its therapeutic development. The cryoelectron microscopy structures of Boc5 and its closely related analog WB4-24 presented here reveal a binding pocket located deeper in the transmembrane domain for nonpeptidic GLP-1R agonists. Molecular interaction with this site may facilitate a broad spectrum of in vivo agonistic activities, in addition to that with the upper helical bundles presumably responsible for biased signaling. These findings deepen our understanding of peptidomimetic agonism at GLP-1R and may help design better drug leads against this important target. Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of these agonists are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric nonpeptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryoelectron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and Gs protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3, and 7, one arm of both compounds was inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8 to D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts, showing an interaction feature substantially similar to the previously known small-molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by nonpeptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine-tuning of pharmacological efficacy in the development of future small-molecule therapeutics targeting GLP-1R.
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影响因子：
3
作者：
Vanommeslaeghe, K.;Hatcher, E.;Acharya, C.;Kundu, S.;Zhong, S.;Shim, J.;Darian, E.;Guvench, O.;Lopes, P.;Vorobyov, I.;MacKerell, A. D., Jr.
通讯作者：
MacKerell, A. D., Jr.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.8
作者：
MontroseRafizadeh, C;Yang, H;Eng, J
通讯作者：
Eng, J
影响因子：
8.1
作者：
Lucey, Maria;Pickford, Philip;Jones, Ben
通讯作者：
Jones, Ben
影响因子：
5.5
作者：
Hess, Berk
通讯作者：
Hess, Berk