Computational model of the full-length TSH receptor
Mihaly Mezei1,2, Rauf Latif2,3, Terry F Davies2,3
1Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.
Elife
|October 28, 2022
Summary
The TSH receptor's flexible linker region is key to its function and response to TSH binding. This finding is crucial for understanding Graves' disease and developing new therapies.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Biology
Background:
- The TSH receptor (TSHR) is a G protein-coupled receptor (GPCR) and the primary antigen in Graves' disease.
- Previous structural studies of TSHR were limited to a single extracellular domain.
- A full-length TSHR model was needed to understand its dynamics and ligand interactions.
Purpose of the Study:
- To generate and simulate a full-length TSHR model.
- To investigate the structural dynamics of the TSHR, particularly the linker region (LR).
- To explore the interaction between the TSHR, its ligand (TSH), and the LR.
Main Methods:
- 1000 ns molecular dynamics simulation of a full-length TSHR model.
- AI-generated extracellular region merged with a homology-modeled transmembrane domain.
- Simulation embedded in a lipid membrane with water and counterions.
Main Results:
- Transmembrane and leucine-rich domains showed structural stability.
- The linker region (LR) exhibited significant flexibility and transient secondary structures.
- The LR demonstrated intrinsic disorder, with variable orientation of the leucine-rich domain.
- TSH binding showed strong affinity for the LR, reducing its structural fluctuations.
Conclusions:
- The linker region (LR) is intrinsically disordered and plays a critical role in TSHR ligand binding.
- The TSHR model provides a foundation for studying TSHR autoantibodies in Graves' disease.
- Understanding the LR's flexibility is essential for elucidating TSHR's role in autoimmune hyperthyroidism.
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