ジャーナル: Nature / 年: 2021 タイトル: Structures of full-length glycoprotein hormone receptor signalling complexes. 著者: Jia Duan / Peiyu Xu / Xi Cheng / Chunyou Mao / Tristan Croll / Xinheng He / Jingjing Shi / Xiaodong Luan / Wanchao Yin / Erli You / Qiufeng Liu / Shuyang Zhang / Hualiang Jiang / Yan Zhang / ...著者: Jia Duan / Peiyu Xu / Xi Cheng / Chunyou Mao / Tristan Croll / Xinheng He / Jingjing Shi / Xiaodong Luan / Wanchao Yin / Erli You / Qiufeng Liu / Shuyang Zhang / Hualiang Jiang / Yan Zhang / Yi Jiang / H Eric Xu / 要旨: Luteinizing hormone and chorionic gonadotropin are glycoprotein hormones that are related to follicle-stimulating hormone and thyroid-stimulating hormone. Luteinizing hormone and chorionic ...Luteinizing hormone and chorionic gonadotropin are glycoprotein hormones that are related to follicle-stimulating hormone and thyroid-stimulating hormone. Luteinizing hormone and chorionic gonadotropin are essential to human reproduction and are important therapeutic drugs. They activate the same G-protein-coupled receptor, luteinizing hormone-choriogonadotropin receptor (LHCGR), by binding to the large extracellular domain. Here we report four cryo-electron microscopy structures of LHCGR: two structures of the wild-type receptor in the inactive and active states; and two structures of the constitutively active mutated receptor. The active structures are bound to chorionic gonadotropin and the stimulatory G protein (G), and one of the structures also contains Org43553, an allosteric agonist. The structures reveal a distinct 'push-and-pull' mechanism of receptor activation, in which the extracellular domain is pushed by the bound hormone and pulled by the extended hinge loop next to the transmembrane domain. A highly conserved 10-residue fragment (P10) from the hinge C-terminal loop at the interface between the extracellular domain and the transmembrane domain functions as a tethered agonist to induce conformational changes in the transmembrane domain and G-protein coupling. Org43553 binds to a pocket of the transmembrane domain and interacts directly with P10, which further stabilizes the active conformation. Together, these structures provide a common model for understanding the signalling of glycoprotein hormone receptors and a basis for drug discovery for endocrine diseases.
履歴
登録
2021年7月31日
登録サイト: PDBJ / 処理サイト: PDBJ
改定 1.0
2021年9月29日
Provider: repository / タイプ: Initial release
改定 1.0
2021年9月29日
Data content type: EM metadata / Data content type: EM metadata / Provider: repository / タイプ: Initial release
改定 1.0
2021年9月29日
Data content type: Image / Data content type: Image / Provider: repository / タイプ: Initial release
改定 1.0
2021年9月29日
Data content type: Primary map / Data content type: Primary map / Provider: repository / タイプ: Initial release
改定 1.0
2021年9月29日
Data content type: Image / Data content type: Image / Provider: repository / タイプ: Initial release
改定 1.0
2021年9月29日
Data content type: Primary map / Data content type: Primary map / Provider: repository / タイプ: Initial release
改定 1.0
2021年9月29日
Data content type: Image / Data content type: Image / Provider: repository / タイプ: Initial release
改定 1.0
2021年9月29日
Data content type: Primary map / Data content type: Primary map / Provider: repository / タイプ: Initial release
Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / カテゴリ: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name