Extended Data Fig. 10: TMD configuration of the TSHR structures.

a, Comparison of HDX-MS analysis on inactivated and active TSHR, differential HDX-MS data consolidated are mapped to active TSHR model according to the differential HDX dynamics key. Regions that show increased HDX activity (more disordered) are coloured yellow/red; regions that show decreased HDX activity (more stable) are coloured green/blue. Comparison of K1-70/Org 274179-TSHR with M22_ScFv–TSHR–G_s complex (right panel), comparison of K1-70/Org 274179-TSHR with M22_ScFv/ML-109–TSHR–G_s complex (left panel). b–e, Structural comparison between inactivated TSHR and active TSHR. Active TSHR structure from TSH–TSHR–G_s complex is shown in orange, active TSHR structure from M22_ScFv–TSHR–G_s complex is shown in green. The inactivated TSHR structure is shown in grey. The two residues M637^6.48 and D633^6.44 are shown in sticks. f, Structural comparisons between β_2AR (PDB: 3SN6) and active TSHR. g, Comparison of inactivated TSHR with ML-109 bound active TSHR. ML-109 clashes with extracellular side of TM6 from the inactivated TSHR structure. h, Comparison the ML-109 binding pocket of TSHR with other orthosteric agonist-binding pockets of class A GPCRs. i, Active TSHR TMD residues locate near the D633^6.44 are shown in sticks.