Sandbox Reserved 1780

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 5: Line 5:
=== Active and Inactive Form ===
=== Active and Inactive Form ===
[[Image:Morph_pics2.png|200 px|right|thumb|Figure 2: Inactive form of the thyrotropin receptor shown in blue. Active form of the thyrotropin receptor shown in green.]]
[[Image:Morph_pics2.png|200 px|right|thumb|Figure 2: 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 2). The <scene name='95/952708/Tshr_chainr_ecd/1'>ECD</scene> protrudes from the cell membrane into the space outside the cell. The <scene name='95/952708/Tshr_chainr_tm/1'>transmembrane 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 <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 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" />
== TSHR Agonists and Antagonists ==
== TSHR Agonists and Antagonists ==
-
Chemical [https://en.wikipedia.org/wiki/Agonist 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 [https://en.wikipedia.org/wiki/Receptor_antagonist 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 researchers to uncover the mechanism of binding for the receptor.
+
Chemical [https://en.wikipedia.org/wiki/Agonist 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 [https://en.wikipedia.org/wiki/Receptor_antagonist 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.<ref name="Miguel"> doi:10.1677/JME-08-0152</ref>.
===M22 Agonist===
===M22 Agonist===
-
<scene name='95/952708/M22_edited/3'>M22</scene> is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that was isolated from a patient with [https://www.niddk.nih.gov/health-information/endocrine-diseases/graves-disease Graves' Disease]. In Graves' disease, TSHR autoantibodies like M22 mimic TSH function and cause thyroid overactivity. <ref name="Miguel"> doi:10.1677/JME-08-0152</ref>. The M22 [https://en.wikipedia.org/wiki/Autoantibody 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). This autoantibody mimics TSH action and binding to TSHR, indicating M22 is a potent activator for TSHR. <ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref> Although M22 binds in a similar manner to TSH, there is a key difference in binding between the two that can reveal the function of the <scene name='95/952709/Hinge_region_real/2'>hinge region</scene>. M22 does not make interactions with the hinge region when bound to TSHR, whereas TSH bound to TSHR does.<ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref> 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. [[Image:Agonist pic.png|450 px|right|thumb|Figure 3: Agonist and antagonist drugs for activating or inactivating the TSHR protein.]]
+
<scene name='95/952708/M22_edited/3'>M22</scene> is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that was isolated from a patient with [https://www.niddk.nih.gov/health-information/endocrine-diseases/graves-disease Graves' Disease]. In Graves' disease, autoantibodies mimic TSH function and cause thyroid overactivity. <ref name="Miguel"> doi:10.1677/JME-08-0152</ref>. The M22 [https://en.wikipedia.org/wiki/Autoantibody 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. <ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref> 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.<ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref> 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. [[Image:Agonist pic.png|450 px|right|thumb|Figure 3: Agonist and antagonist drugs for activating or inactivating the TSHR protein.]]
===CS-17 Inverse Agonist===
===CS-17 Inverse Agonist===
Line 20: Line 20:
Thyroid-stimulating hormone <scene name='95/952708/Tsh_7t9i/1'>(TSH)</scene>, 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 <ref name="Duan"> DOI:10.1038/s41586-022-05173-3</ref>. (Figure 3). This clash is caused by glycosylations of an N52 residue on the <scene name='95/952707/Tsh_7t9i/1'>alpha subunit of TSH</scene>. 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.
Thyroid-stimulating hormone <scene name='95/952708/Tsh_7t9i/1'>(TSH)</scene>, 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 <ref name="Duan"> DOI:10.1038/s41586-022-05173-3</ref>. (Figure 3). This clash is caused by glycosylations of an N52 residue on the <scene name='95/952707/Tsh_7t9i/1'>alpha subunit of TSH</scene>. 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.
-
===ML109===
+
 

Revision as of 20:21, 10 April 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.
To get started:
  • Click the edit this page tab at the top. Save the page after each step, then edit it again.
  • show the Scene authoring tools, create a molecular scene, and save it. Copy the green link into the page.
  • Add a description of your scene. Use the buttons above the wikitext box for bold, italics, links, headlines, etc.

More help: Help:Editing

Thyroid stimulating hormone receptor bound to thyroid stimulating hormone

Drag the structure with the mouse to rotate

References

  1. ↑ 1.0 1.1 1.2 1.3 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. ↑ 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. ↑ 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
  4. ↑ 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
Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1780"
Personal tools