Structure of full-length TSH receptor in complex with antibody K1-70™

Area of Science:

• Structural Biology
• Endocrinology
• Molecular Medicine

Background:

• The thyroid-stimulating hormone receptor (TSHR) is crucial for thyroid hormone production.
• Understanding TSHR structure is key to deciphering its regulation and associated diseases.

Purpose of the Study:

• To determine the full-length TSHR structure in complex with an inhibitory autoantibody.
• To elucidate the structural basis for TSHR autoantibody binding and modulation of receptor activity.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to resolve the TSHR structure at 3.3 Å resolution.
• Detergent solubilization and purification of the TSHR-autoantibody complex.

Main Results:

• The TSHR structure reveals distinct extracellular (leucine-rich and hinge regions) and transmembrane domains.
• Analysis explains how TSHR mutations affect constitutive and ligand-induced activity.
• The inhibitory autoantibody K1-70™ binds without activating the receptor, while the stimulatory M22™ antibody may require hinge region rotation.

Conclusions:

• The determined TSHR structure provides a molecular basis for understanding autoantibody interactions.
• Structural insights explain the differential effects of inhibitory versus stimulatory autoantibodies on TSHR function.
• This work offers a framework for designing TSHR-targeting therapeutics.