Sandbox Reserved 1780

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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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Thyroid stimulating hormone receptor bound to thyroid stimulating hormone

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1 Active and Inactive Form
2 TSHR Agonists and Antagonists

Active and Inactive Form

Figure 2: Inactive form of the thyrotropin receptor shown in blue (PDB: 7T9M). Active form of the thyrotropin receptor shown in green (PDB: 7T9I).

The TSHR protein exists in two states: active and inactive (Figure 2). The exists in dynamic equilibrium where binding favors the active state. In this active state, TSH will bind and keep the active state in the up position because of clashes between bound TSH and the cell membrane.^[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.^[2].

M22 Agonist

is a monoclonal antibody that was isolated from a patient with Graves' Disease. In Graves' disease, autoantibodies mimic TSH function and cause thyroid overactivity. ^[2]. The M22 autoantibody activates TSHR by causing a membrane clash with the ECD and cell membrane, keeping the TSHR in the active state by preventing the TSHR from rotating to the inactive state (Figure 3). M22 mimics TSH activation of TSHR because it is a potent activator for TSHR. ^[1] Although M22 binds in a similar manner to TSH, M22 does not interact with the hinge region when bound to TSHR, whereas TSH bound to TSHR does.^[1] This finding shows that the hinge region is not necessary for the activation of TSHR, and leads to the discovery of other methods of activation.

Figure 3: Agonist and antagonist drugs for activating or inactivating the TSHR protein.

CS-17 Inverse Agonist

is a monoclonal antibody that acts as an inverse agonist for TSHR constitutive activity. ^[3]. CS-17 interacts with the ECD of the TSHR protein on the convex side of the LRRD. When bound to TSHR, CS-17 suppresses TSHR function by keeping the receptor in the inactive state (Figure 3). Clash with the cell membrane does not allow the inactive form of TSHR to flip to the active conformation. CS-17 plays a unique role with GPCRs. This type of inhibition is not commonly seen in many biological systems and therefore leads to this method of inhibition being a great target for drug design and future research.^[3]. Due to its unique inhibition, CS-17 can be a popular therapy for many thyroid diseases where the thyroid is overactive.

TSH Agonist

Figure 4

Thyroid-stimulating hormone , as previously mentioned, is a hormone that stimulates the thyroid gland to produce proteins that are vital for many metabolic pathways in the body's tissue. TSH activates the TSHR protein by binding to the concave surface of the LRRD and hinge region to keep TSHR in its active state by clashing with the membrane ^[4]. (Figure 3). This clash is caused by glycosylations of an N52 residue on the . These modifications to the N residue are N-acetyl glucosamine modifications (Figure 4). They stick out from the alpha subunit of TSH to clash with the cell membrane and keep TSH in the active state.

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
↑ ^2.0 ^2.1 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
↑ ^3.0 ^3.1 Chen, C.-R., McLachlan, S. M., & Rapoport, B. (2007). Suppression of thyrotropin receptor constitutive activity by a monoclonal antibody with inverse agonist activity. Endocrinology, 148(5), 2375–2382. https://doi.org/10.1210/en.2006-1754
↑ Duan J, Xu P, Luan X, Ji Y, He X, Song N, Yuan Q, Jin Y, Cheng X, Jiang H, Zheng J, Zhang S, Jiang Y, Xu HE. Hormone- and antibody-mediated activation of the thyrotropin receptor. Nature. 2022 Aug 8. pii: 10.1038/s41586-022-05173-3. doi:, 10.1038/s41586-022-05173-3. PMID:35940204 doi:http://dx.doi.org/10.1038/s41586-022-05173-3

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@@ Line 5: / Line 5: @@
 === Active and Inactive Form ===
 [[Image:Morphmembrane.png|450 px|right|thumb|Figure 2: Inactive form of the thyrotropin receptor shown in blue (PDB: 7T9M). Active form of the thyrotropin receptor shown in green (PDB: 7T9I).]]
-The TSHR protein exists in two states: active and inactive (Figure 2). The <scene name='95/952708/Tshr_chainr/4'>TSHR active form</scene> exists when bound to the <scene name='95/952708/Tsh_7t9i/1'>TSH</scene>. One proposed mechanism for the transition from the active to inactive describes that in a 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" /> 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" />
+The TSHR protein exists in two states: active and inactive (Figure 2). The <scene name='95/952708/Tshr_chainr/4'>TSHR active form</scene> exists in dynamic equilibrium where <scene name='95/952708/Tsh_7t9i/1'>TSH</scene> binding favors the active state. In this active state, TSH will bind and keep the active state in the up position because of clashes between bound TSH and the cell membrane.<ref name="Faust" />.
 == TSHR Agonists and Antagonists ==

Sandbox Reserved 1780

From Proteopedia

Revision as of 20:47, 10 April 2023

Contents

Active and Inactive Form

TSHR Agonists and Antagonists

M22 Agonist

CS-17 Inverse Agonist

TSH Agonist

References

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