7T9M

Human Thyrotropin receptor bound by CS-17 Inverse Agonist Fab/Org 274179-0 Antagonist

7T9M の概要

• エントリーDOI: 10.2210/pdb7t9m/pdb
• EMDBエントリー: 25762
• 分子名称: CS-17 Heavy Chain, CS-17 Light Chain, Thyrotropin receptor, ... (5 entities in total)
• 機能のキーワード: g protein-coupled receptor, thyroid-stimulating hormone receptor, thyrotropin receptor, cs-17 fab, thyroid, membrane protein
• 由来する生物種: Mus musculus (mouse); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 127392.03

構造登録者

Faust, B.,Cheng, Y.,Manglik, A. (登録日: 2021-12-19, 公開日: 2022-08-10, 最終更新日: 2024-10-09)

主引用文献

Faust, B.,Billesbolle, C.B.,Suomivuori, C.M.,Singh, I.,Zhang, K.,Hoppe, N.,Pinto, A.F.M.,Diedrich, J.K.,Muftuoglu, Y.,Szkudlinski, M.W.,Saghatelian, A.,Dror, R.O.,Cheng, Y.,Manglik, A.
Autoantibody mimicry of hormone action at the thyrotropin receptor.
Nature, 609:846-853, 2022

PubMed Abstract: Thyroid hormones are vital in metabolism, growth and development. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR). In patients with Graves' disease, autoantibodies that activate the TSHR pathologically increase thyroid hormone activity. How autoantibodies mimic thyrotropin function remains unclear. Here we determined cryo-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. Thyrotropin selects an upright orientation of the extracellular domain owing to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody from a patient with Graves' disease selects a similar upright orientation of the extracellular domain. Reorientation of the extracellular domain transduces a conformational change in the seven-transmembrane-segment domain via a conserved hinge domain, a tethered peptide agonist and a phospholipid that binds within the seven-transmembrane-segment domain. Rotation of the TSHR extracellular domain relative to the membrane bilayer is sufficient for receptor activation, revealing a shared mechanism for other glycoprotein hormone receptors that may also extend to other G-protein-coupled receptors with large extracellular domains.

PubMed: 35940205
DOI: 10.1038/s41586-022-05159-1

実験手法

ELECTRON MICROSCOPY (3.1 Å)