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-Structure paper
タイトル | Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor. |
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ジャーナル・号・ページ | Nat Commun, Vol. 14, Issue 1, Page 519, Year 2023 |
掲載日 | 2023年1月31日 |
著者 | Jia Duan / Peiyu Xu / Huibing Zhang / Xiaodong Luan / Jiaqi Yang / Xinheng He / Chunyou Mao / Dan-Dan Shen / Yujie Ji / Xi Cheng / Hualiang Jiang / Yi Jiang / Shuyang Zhang / Yan Zhang / H Eric Xu / |
PubMed 要旨 | Follicle stimulating hormone (FSH) is an essential glycoprotein hormone for human reproduction, which functions are mediated by a G protein-coupled receptor, FSHR. Aberrant FSH-FSHR signaling causes ...Follicle stimulating hormone (FSH) is an essential glycoprotein hormone for human reproduction, which functions are mediated by a G protein-coupled receptor, FSHR. Aberrant FSH-FSHR signaling causes infertility and ovarian hyperstimulation syndrome. Here we report cryo-EM structures of FSHR in both inactive and active states, with the active structure bound to FSH and an allosteric agonist compound 21 f. The structures of FSHR are similar to other glycoprotein hormone receptors, highlighting a conserved activation mechanism of hormone-induced receptor activation. Compound 21 f formed extensive interactions with the TMD to directly activate FSHR. Importantly, the unique residue H615 in FSHR plays an essential role in determining FSHR selectivity for various allosteric agonists. Together, our structures provide a molecular basis of FSH and small allosteric agonist-mediated FSHR activation, which could inspire the design of FSHR-targeted drugs for the treatment of infertility and controlled ovarian stimulation for in vitro fertilization. |
リンク | Nat Commun / PubMed:36720854 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.8 - 6.0 Å |
構造データ | EMDB-35135, PDB-8i2g: EMDB-35136, PDB-8i2h: |
化合物 | ChemComp-CLR: ChemComp-PLM: ChemComp-MYR: ChemComp-NAG: ChemComp-O6F: |
由来 |
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キーワード | HORMONE / Follicle stimulating hormone / FSH / GPCR / Gs-protein / FSHR |