Sandbox Reserved 1774

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This Sandbox is Reserved from February 27 through August 31, 2023 for use in the course CH462 Biochemistry II taught by R. Jeremy Johnson at the Butler University, Indianapolis, USA. This reservation includes Sandbox Reserved 1765 through Sandbox Reserved 1795.

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1 Thyroid Stimulating Hormone Receptor (TSHR) Structure and Function

Thyroid Stimulating Hormone Receptor (TSHR) Structure and Function

Introduction

In humans, the hypothalamic-pituitary-thyroid (HPT) signaling axis regulates functions including metabolism, growth, organ development, and neural differentiation ^[1]. In this pathway, the thyroid stimulating hormone receptor (TSHR) activates transcription of thyroid hormones in response to ligand binding by thyroid stimulating hormone (TSH). After a brief introduction to the biological significance of TSHR, this page explores the structure of TSHR and its significance to TSH binding and receptor activation.

Biological Significance of TSHR

The HPT signaling axis involves the brain, thyroid gland, and bloodstream circulation. In the first step of the pathway, thyrotropin releasing hormone (TRH) is secreted by the hypothalamus, which in turn stimulates the anterior pituitary gland to produce TSH ^[1]. TSH binds to TSHR on the surface of thyroid cells and triggers the production of thyroid hormones thyroxine (T3) and triiodothyronine (T4) through G-protein coupled receptor (GPCR) signaling ^[2]. T3 and T4 are released into the bloodstream circulation and help to regulate metabolism, including through negative feedback loop inhibition of further TSH production ^[1].

The Malfunction of TSHR, or its TSH ligand, can lead to disease. In Grave's disease, production of a

Structural Overview of TSHR

Describe the domains here.

TSHR Activation

Hinge Motion

Describe the hinge motion and biological function here. This shows the TSHR hinge movement. This shows the TSHR hinge movement. .

Image:TSHR MorphBetterAngle.mp4

Stabilizing Interactions in the Hinge

Describe important structural features of the hinge here.

Ligand Binding

Ligand-induced Conformation Change

Describe how TSH binds in the upright conformation here.

Ligand Recognition

Describe seatbelt and hinge important to ligand recognition here.

References

↑ ^1.0 ^1.1 ^1.2 Brent GA. Mechanisms of thyroid hormone action. J Clin Invest. 2012 Sep;122(9):3035-43. PMID:22945636 doi:10.1172/JCI60047
↑ Chu YD, Yeh CT. The Molecular Function and Clinical Role of Thyroid Stimulating Hormone Receptor in Cancer Cells. Cells. 2020 Jul 20;9(7):1730. PMID:32698392 doi:10.3390/cells9071730

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 == Introduction ==
-In humans, the hypothalamic-pituitary-thyroid (HPT) signaling axis regulates functions including metabolism, growth, organ development, and neural differentiation <ref name="Brent">PMID:22945636</ref>. In this pathway, the thyroid stimulating hormone receptor (TSHR) activates transcription of thyroid hormones in response to ligand binding by thyroid stimulating hormone (TSH). After a brief introduction to the biological significance of TSHR, this page explores the structure of TSHR and its significance to TSH binding and receptor activation.
+In humans, the hypothalamic-pituitary-thyroid (HPT) signaling axis regulates functions including metabolism, growth, organ development, and neural differentiation <ref name="Brent">DOI: 10.1172/JCI60047</ref>. In this pathway, the thyroid stimulating hormone receptor (TSHR) activates transcription of thyroid hormones in response to ligand binding by thyroid stimulating hormone (TSH). After a brief introduction to the biological significance of TSHR, this page explores the structure of TSHR and its significance to TSH binding and receptor activation.
 == Biological Significance of TSHR ==
-The HPT signaling axis involves the brain, thyroid gland, and bloodstream circulation. In the first step of the pathway, thyrotropin releasing hormone (TRH) is secreted by the hypothalamus, which in turn stimulates the anterior pituitary gland to produce TSH <ref name="Brent" />. TSH binds to TSHR on the surface of thyroid cells and triggers the production of thyroid hormones thyroxine (T3) and triiodothyronine (T4) through G-protein coupled receptor (GPCR) signaling <ref name="Chu">PMID:32698392</ref>. T3 and T4 are released into the bloodstream circulation and help to regulate metabolism, including through negative feedback loop inhibition of further TSH production <ref name="Brent" />.
+The HPT signaling axis involves the brain, thyroid gland, and bloodstream circulation. In the first step of the pathway, thyrotropin releasing hormone (TRH) is secreted by the hypothalamus, which in turn stimulates the anterior pituitary gland to produce TSH <ref name="Brent" />. TSH binds to TSHR on the surface of thyroid cells and triggers the production of thyroid hormones thyroxine (T3) and triiodothyronine (T4) through G-protein coupled receptor (GPCR) signaling <ref name="Chu">DOI: 10.3390/cells9071730</ref>. T3 and T4 are released into the bloodstream circulation and help to regulate metabolism, including through negative feedback loop inhibition of further TSH production <ref name="Brent" />.
 The Malfunction of TSHR, or its TSH ligand, can lead to disease. In Grave's disease, production of a