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日本东京大学Osamu Nureki等研究人员合作揭示细胞内激动剂对B1类GPCR的激活。2023年6月7日，《自然》杂志在线发表了这项成果。

研究人员报告了G_s和人类甲状旁腺激素1型受体（PTH1R）与PTH1R激动剂PCO371结合的复合物冷冻电镜结构。PCO371结合在PTH1R的一个细胞内口袋内，并与G_s直接相互作用。PCO371的结合方式使细胞内区域向活性构象重新排列，而不需要细胞外诱导的异构信号传播。PCO371稳定了跨膜螺旋6的明显向外弯曲的构象，这有利于与G蛋白而不是β-抑制素结合。此外，PCO371在高度保守的细胞内口袋内结合，激活了15个B1类G蛋白偶联受体（GPCR）中的7个。这项研究确定了一个新的和保守的细胞内激动剂结合口袋，并提供了靶向受体-转导蛋白界面的偏向信号机制的证据。

据了解，GPCR通常在正构结合袋中容纳特定配体。配体结合引发受体的异生构象变化，导致细胞内转导因子、G蛋白和β-抑制素的激活。由于这些信号经常诱发不利影响，必须阐明每个转导因子的选择性激活机制。因此，人们已经开发了许多正构性偏向的激动剂，而细胞内偏向的激动剂最近引起了广泛的兴趣。这些激动剂在受体的细胞内腔内结合，优先调整特定的信号通路，而不是其他信号通路，这不需要从细胞外侧对受体进行变构重排。然而，目前只有拮抗剂结合的结构可用，没有证据支持偏向性激动剂结合发生在细胞内腔。这限制了对细胞内偏向激动剂的理解和潜在药物的开发。

附：英文原文

Title: Class B1 GPCR activation by an intracellular agonist

Author: Kobayashi, Kazuhiro, Kawakami, Kouki, Kusakizako, Tsukasa, Tomita, Atsuhiro, Nishimura, Michihiro, Sawada, Kazuhiro, Okamoto, Hiroyuki H., Hiratsuka, Suzune, Nakamura, Gaku, Kuwabara, Riku, Noda, Hiroshi, Muramatsu, Hiroyasu, Shimizu, Masaru, Taguchi, Tomohiko, Inoue, Asuka, Murata, Takeshi, Nureki, Osamu

Issue&Volume: 2023-06-07

Abstract: Gprotein-coupled receptors (GPCRs) generally accommodate specific ligands in the orthosteric-binding pockets. Ligand binding triggers a receptor allosteric conformational change that leads to the activation of intracellular transducers, Gproteins and β-arrestins. Because these signals often induce adverse effects, the selective activation mechanism for each transducer must be elucidated. Thus, many orthosteric-biased agonists have been developed, and intracellular-biased agonists have recently attracted broad interest. These agonists bind within the receptor intracellular cavity and preferentially tune the specific signalling pathway over other signalling pathways, without allosteric rearrangement of the receptor from the extracellular side1,2,3. However, only antagonist-bound structures are currently available1,4,5,6, and there is no evidence to support that biased agonist binding occurs within the intracellular cavity. This limits the comprehension of intracellular-biased agonism and potential drug development. Here we report the cryogenic electron microscopy structure of a complex of Gs and the human parathyroid hormone type1 receptor (PTH1R) bound to a PTH1R agonist, PCO371. PCO371 binds within an intracellular pocket of PTH1R and directly interacts with Gs. The PCO371-binding mode rearranges the intracellular region towards the active conformation without extracellularly induced allosteric signal propagation. PCO371 stabilizes the significantly outward-bent conformation of transmembrane helix6, which facilitates binding to Gproteins rather than β-arrestins. Furthermore, PCO371 binds within the highly conserved intracellular pocket, activating 7 out of the 15 class B1 GPCRs. Our study identifies a new and conserved intracellular agonist-binding pocket and provides evidence of a biased signalling mechanism that targets the receptor–transducer interface.

DOI: 10.1038/s41586-023-06169-3

Source: https://www.nature.com/articles/s41586-023-06169-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html