Sandbox Reserved 1780

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(Difference between revisions)

Revision as of 20:21, 29 March 2023

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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Thyroid stimulating hormone receptor bound to thyroid stimulating hormone

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Active and Inactive Form

Figure 1: Inactive form of the thyrotropin receptor shown in blue. Active form of the thyrotropin receptor shown in green.

The TSHR protein exists in two states, active and inactive (Figure 1). The extracellular domain sticks out from the cell membrane into the space outside the cell. The contains 7 alpha helices that reside within the cell membrane. The exists when bound to the thyroid stimulating hormone (TSH) (GREEN LINK). One proposed mechanism for the transition from the active to inactive describes that in its natural state, the TSHR ECD can spontaneously transition to the up state, leading to constitutive activity. In this active state, TSH will bind and keep the active state in the up position because of clash with the cell membrane.^[1] Conformational change of ECD allows for signal transduction through the TM and into the cell. The ECD rotates 55 degrees up in the active form. ^[1]

TSHR Agonists and Antagonists

Chemical agonists are found in many living systems and serve as a way to activate receptors or pathways that are necessary for a wide array of biological processes. Chemical antagonists block or inhibit biological processes. Different types of agonists/antagonists exist within the body including hormones, antibodies, and neurotransmitters. The body naturally produces autoantibodies that can act as agonists and mimic the activating mechanism of the natural hormone. Isolating these antibodies in patients with diseases can lead researches to uncover the mechanism of binding for the receptor.

M22 Agonist

M22 is a monoclonal antibody that was isolated from a patient with Graves' Disease. In Graves' disease TSHR autoantibodies like M22 mimic TSH function and cause thyroid overactivity. ^[2]. The M22 autoantibody activates TSHR by causing a membrane clash with the ECD and cell membrane, therefore keeping the TSHR in the activate state by preventing the TSHR from rotating to the inactive state (Figure 2). This autoantibody mimics TSH action and binding to TSHR resulting in a potent activator for TSHR. ^[1]

Figure 2: Agonist and antagonist drugs for activating or inactivating the TSHR protein.

References

↑ ^1.0 ^1.1 ^1.2 Faust B, Billesbolle CB, Suomivuori CM, Singh I, Zhang K, Hoppe N, Pinto AFM, Diedrich JK, Muftuoglu Y, Szkudlinski MW, Saghatelian A, Dror RO, Cheng Y, Manglik A. Autoantibody mimicry of hormone action at the thyrotropin receptor. Nature. 2022 Aug 8. pii: 10.1038/s41586-022-05159-1. doi:, 10.1038/s41586-022-05159-1. PMID:35940205 doi:http://dx.doi.org/10.1038/s41586-022-05159-1
↑ Nunez Miguel R, Sanders J, Chirgadze DY, Furmaniak J, Rees Smith B. Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein-protein interactions. J Mol Endocrinol. 2009 May;42(5):381-95. Epub 2009 Feb 16. PMID:19221175 doi:10.1677/JME-08-0152

Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1780"

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 == Active and Inactive Form ==
 [[Image:Morph_pics2.png|200 px|right|thumb|Figure 1: Inactive form of the thyrotropin receptor shown in blue. Active form of the thyrotropin receptor shown in green.]]
-The TSHR protein exists in two states, active and inactive (Figure 1). The extracellular domain <scene name='95/952708/Ecd/3'>(ECD)</scene> sticks out from the cell membrane into the space outside the cell. The <scene name='95/952709/7tm_helices/4'>7TM domain</scene> contains 7 alpha helices that reside within the cell membrane. The <scene name='95/952708/Tshr_chainr/4'>TSHR active form</scene> exists when bound to the thyroid stimulating hormone (TSH) (GREEN LINK). One proposed mechanism for the transition from the active to inactive describes that in its natural state, the TSHR ECD can spontaneously transition to the up state, leading to constitutive activity. In this active state, TSH will bind and keep the active state in the up position because of clash with the cell membrane.<ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref> Conformational change of ECD allows for signal transduction through the TM and into the cell. The ECD rotates 55 degrees up in the active form. <ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref>
+The TSHR protein exists in two states, active and inactive (Figure 1). The extracellular domain <scene name='95/952708/Ecd/4'>(ECD)</scene> sticks out from the cell membrane into the space outside the cell. The <scene name='95/952709/7tm_helices/4'>7TM domain</scene> contains 7 alpha helices that reside within the cell membrane. The <scene name='95/952708/Tshr_chainr/4'>TSHR active form</scene> exists when bound to the thyroid stimulating hormone (TSH) (GREEN LINK). One proposed mechanism for the transition from the active to inactive describes that in its natural state, the TSHR ECD can spontaneously transition to the up state, leading to constitutive activity. In this active state, TSH will bind and keep the active state in the up position because of clash with the cell membrane.<ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref> Conformational change of ECD allows for signal transduction through the TM and into the cell. The ECD rotates 55 degrees up in the active form. <ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref>
 == TSHR Agonists and Antagonists ==

Sandbox Reserved 1780

From Proteopedia

Revision as of 20:21, 29 March 2023

Active and Inactive Form

TSHR Agonists and Antagonists

M22 Agonist

References

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