7XW6

TSHR-Gs-M22 antibody-ML109 complex

Summary for 7XW6

• Entry DOI: 10.2210/pdb7xw6/pdb
• EMDB information: 33492
• Descriptor: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, PALMITIC ACID, ~{N}-[4-[[2-methoxy-5-[(2~{S})-5-oxidanyl-4-oxidanylidene-3-(phenylmethyl)-1,2-dihydroquinazolin-2-yl]phenyl]methoxy]phenyl]ethanamide, ... (11 entities in total)
• Functional Keywords: thyroid-stimulating hormone, thyroid-stimulating hormone receptor, ths, thsr, gpcr, gs, ml-109, m22, scfv, membrane protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 7
• Total formula weight: 204812.04

Authors

Duan, J.,Xu, P.,Luan, X.,Ji, Y.,Yuan, Q.,He, X.,Ye, J.,Cheng, X.,Jiang, H.,Zhang, S.,Jiang, Y.,Xu, H.E. (deposition date: 2022-05-26, release date: 2022-08-17, Last modification date: 2024-10-09)

Primary citation

Duan, J.,Xu, P.,Luan, X.,Ji, Y.,He, X.,Song, N.,Yuan, Q.,Jin, Y.,Cheng, X.,Jiang, H.,Zheng, J.,Zhang, S.,Jiang, Y.,Xu, H.E.
Hormone- and antibody-mediated activation of the thyrotropin receptor.
Nature, 609:854-859, 2022

PubMed Abstract: Thyroid-stimulating hormone (TSH), through activation of its G-protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone-an essential metabolic hormone. Aberrant signalling of TSHR by autoantibodies causes Graves' disease (hyperthyroidism) and hypothyroidism, both of which affect millions of patients worldwide. Here we report the active structures of TSHR with TSH and the activating autoantibody M22, both bound to the allosteric agonist ML-109, as well as an inactivated TSHR structure with the inhibitory antibody K1-70. Both TSH and M22 push the extracellular domain (ECD) of TSHR into an upright active conformation. By contrast, K1-70 blocks TSH binding and cannot push the ECD into the upright conformation. Comparisons of the active and inactivated structures of TSHR with those of the luteinizing hormone/choriogonadotropin receptor (LHCGR) reveal a universal activation mechanism of glycoprotein hormone receptors, in which a conserved ten-residue fragment (P10) from the hinge C-terminal loop mediates ECD interactions with the TSHR transmembrane domain. One notable feature is that there are more than 15 cholesterols surrounding TSHR, supporting its preferential location in lipid rafts. These structures also highlight a similar ECD-push mechanism for TSH and autoantibody M22 to activate TSHR, therefore providing the molecular basis for Graves' disease.

PubMed: 35940204
DOI: 10.1038/s41586-022-05173-3

Experimental method

ELECTRON MICROSCOPY (2.78 Å)