Computational model of the full-length TSH receptor

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Abstract

The receptor for thyroid stimulating hormone (TSHR), a GPCR, is of particular interest as the primary antigen in autoimmune hyperthyroidism (Graves' disease) caused by stimulating TSHR antibodies. To date, only one domain of the extracellular region of the TSHR has been crystallized. We have run a 1000ns Molecular Dynamic simulation on a model of the entire TSHR generated by merging the extracellular region of the receptor, obtained using artificial intelligence, with our recent homology model of the transmembrane domain, embedded it in a lipid membrane solvated it with water and counterions. The simulations showed that the structure of the transmembrane and leucine-rich domains were remarkably constant while the linking region (LR), known more commonly as the 'hinge region', showed significant flexibility, forming several transient secondary structural elements. Furthermore, the relative orientation of the leucine-rich domain with the rest of the receptor was also seen to be variable. These data suggest that this linker region is an intrinsically disordered protein (IDP). Furthermore, preliminary data simulating the full TSHR model complexed with its ligand (TSH) showed that (a) there is a strong affinity between the linker region and TSH ligand and (b) the association of the linker region and the TSH ligand reduces the structural fluctuations in the linker region. This full-length model illustrates the importance of the linker region in responding to ligand binding and lays the foundation for studies of pathologic TSHR autoantibodies complexed with the TSHR to give further insight into their interaction with the flexible linker region.

Data availability

The initial model generated is available from the Dryad server; URL: https://doi.org/10.5061/dryad.rjdfn2zdp.The software used for the analysis are available at the URL https://mezeim01.u.hpc.mssm.edu

The following data sets were generated

1. Mezei
2. et al
(2022) Data from: Computational model of the full-length TSH receptor
Dryad Digital Repository, doi:10.5061/dryad.rjdfn2zdp.

http://dx.doi.org/10.5061/dryad.rjdfn2zdp

The following previously published data sets were used

1. Jumper RE
2. et al
(2021) Swissprot/Uniprot
/P1/64/73.

https://web.expasy.org
1. Mezei M
2. Latif R
3. Das B
4. Davies TF
(2021) An improved computational model of the transmembrane domain of the thyroid stimulating hormone receptor
TMD3.

https://mezeim01.u.hps.mssm.edu/prod/TMD3

Article and author information

Author details

Mihaly Mezei

Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States

For correspondence
Mihaly.Mezei@mssm.edu

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-0294-4307
Rauf Latif

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-4226-3728
Terry F Davies

Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States

Competing interests
Terry F Davies, is member of the Board of Kronus Inc (Starr, ID, USA); MM, and RF have nothing to disclose..

Funding

NIH Office of the Director (DK069713)

Mihaly Mezei

Veterans Administration merit award (BX000800)

Terry F Davies

Segal Family Foundation (00000000)

Terry F Davies

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.