7T9M
Human Thyrotropin receptor bound by CS-17 Inverse Agonist Fab/Org 274179-0 Antagonist
Summary for 7T9M
| Entry DOI | 10.2210/pdb7t9m/pdb |
| EMDB information | 25762 |
| Descriptor | CS-17 Heavy Chain, CS-17 Light Chain, Thyrotropin receptor, ... (5 entities in total) |
| Functional Keywords | g protein-coupled receptor, thyroid-stimulating hormone receptor, thyrotropin receptor, cs-17 fab, thyroid, membrane protein |
| Biological source | Mus musculus (mouse) More |
| Total number of polymer chains | 3 |
| Total formula weight | 127392.03 |
| Authors | Faust, B.,Cheng, Y.,Manglik, A. (deposition date: 2021-12-19, release date: 2022-08-10, Last modification date: 2024-10-09) |
| Primary citation | 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 Cited by 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: 35940205DOI: 10.1038/s41586-022-05159-1 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.1 Å) |
Structure validation
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