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Computational model of the full-length TSH receptor

(GPCR)The receptor for TSH receptor (TSHR), a G protein coupled receptor (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 crystalli...

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Autores principales: Mezei, Mihaly, Latif, Rauf, Davies, Terry F
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9640187/
https://www.ncbi.nlm.nih.gov/pubmed/36305581
http://dx.doi.org/10.7554/eLife.81415
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author Mezei, Mihaly
Latif, Rauf
Davies, Terry F
author_facet Mezei, Mihaly
Latif, Rauf
Davies, Terry F
author_sort Mezei, Mihaly
collection PubMed
description (GPCR)The receptor for TSH receptor (TSHR), a G protein coupled receptor (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 1000 ns 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 and solvated it with water and counterions. The simulations showed that the structure of the transmembrane and leucine-rich domains were remarkably constant while the linker 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 LR is an intrinsically disordered protein. Furthermore, preliminary data simulating the full TSHR model complexed with its ligand (TSH) showed that (a) there is a strong affinity between the LR and TSH ligand and (b) the association of the LR and the TSH ligand reduces the structural fluctuations in the LR. This full-length model illustrates the importance of the LR 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 LR.
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spelling pubmed-96401872022-11-08 Computational model of the full-length TSH receptor Mezei, Mihaly Latif, Rauf Davies, Terry F eLife Structural Biology and Molecular Biophysics (GPCR)The receptor for TSH receptor (TSHR), a G protein coupled receptor (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 1000 ns 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 and solvated it with water and counterions. The simulations showed that the structure of the transmembrane and leucine-rich domains were remarkably constant while the linker 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 LR is an intrinsically disordered protein. Furthermore, preliminary data simulating the full TSHR model complexed with its ligand (TSH) showed that (a) there is a strong affinity between the LR and TSH ligand and (b) the association of the LR and the TSH ligand reduces the structural fluctuations in the LR. This full-length model illustrates the importance of the LR 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 LR. eLife Sciences Publications, Ltd 2022-10-28 /pmc/articles/PMC9640187/ /pubmed/36305581 http://dx.doi.org/10.7554/eLife.81415 Text en © 2022, Mezei et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Structural Biology and Molecular Biophysics
Mezei, Mihaly
Latif, Rauf
Davies, Terry F
Computational model of the full-length TSH receptor
title Computational model of the full-length TSH receptor
title_full Computational model of the full-length TSH receptor
title_fullStr Computational model of the full-length TSH receptor
title_full_unstemmed Computational model of the full-length TSH receptor
title_short Computational model of the full-length TSH receptor
title_sort computational model of the full-length tsh receptor
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9640187/
https://www.ncbi.nlm.nih.gov/pubmed/36305581
http://dx.doi.org/10.7554/eLife.81415
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