Sandbox Reserved 1779: Difference between revisions

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=== 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.]]

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 TSH ~~(GREEN LINK)~~. 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_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" />

== TSHR Agonists and Antagonists ==

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===M22 Agonist===

<scene name='95/952708/~~M22~~/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 hinge region (GREEN LINK). 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, 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 hinge region (GREEN LINK). 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.]]

===CS-17 Inverse Agonist===

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===TSH Agonist===

[[Image:NAG.png|200 px|left|thumb|Figure 4]]

TSH ~~(GREEN LINK~~), 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 alpha subunit of TSH (GREEN LINK). 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 alpha subunit of TSH (GREEN LINK). 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.

Sandbox Reserved 1779: Difference between revisions

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@@ Line 27: / Line 27: @@
 === 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.]]
-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 TSH (GREEN LINK). 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_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" />
 == TSHR Agonists and Antagonists ==
@@ Line 33: / Line 33: @@
 ===M22 Agonist===
-<scene name='95/952708/M22/3'>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 hinge region (GREEN LINK). 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, 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 hinge region (GREEN LINK). 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.]]
 ===CS-17 Inverse Agonist===
@@ Line 40: / Line 40: @@
 ===TSH Agonist===
 [[Image:NAG.png|200 px|left|thumb|Figure 4]]
-TSH (GREEN LINK), 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 alpha subunit of TSH (GREEN LINK). 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 alpha subunit of TSH (GREEN LINK). 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.