Sandbox Reserved 1779: Difference between revisions

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

<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.]]

===CS-17 Inverse Agonist===

CS-17 (GREEN LINK) is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that acts as an inverse agonist for TSHR constitutive activity. <ref name="Chen"> DOI:10.1210/en.2006-1754</ref>. 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 2). 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.<ref name="Chen">doi:10.1210/en.2006-1754</ref>. Due to its unique inhibition, CS-17 can be a popular therapy for many thyroid diseases where the thyroid is overactive.

CS-17 (GREEN LINK) is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that acts as an inverse agonist for TSHR constitutive activity. <ref name="Chen"> DOI:10.1210/en.2006-1754</ref>. 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.<ref name="Chen">doi:10.1210/en.2006-1754</ref>. Due to its unique inhibition, CS-17 can be a popular therapy for many thyroid diseases where the thyroid is overactive.

===TSH Agonist===

[[Image:NAG.png|200 px|left|thumb|Figure 3]]

[[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 2). 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 3). They stick out from the alpha subunit of TSH to clash with the cell membrane and keep TSH in the active state.

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.

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@@ 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 2). 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 2: Agonist and antagonist drugs for activating or inactivating the TSHR protein.]]
+<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.]]
 ===CS-17 Inverse Agonist===
-CS-17 (GREEN LINK) is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that acts as an inverse agonist for TSHR constitutive activity. <ref name="Chen"> DOI:10.1210/en.2006-1754</ref>. 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 2). 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.<ref name="Chen">doi:10.1210/en.2006-1754</ref>. Due to its unique inhibition, CS-17 can be a popular therapy for many thyroid diseases where the thyroid is overactive.
+CS-17 (GREEN LINK) is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that acts as an inverse agonist for TSHR constitutive activity. <ref name="Chen"> DOI:10.1210/en.2006-1754</ref>. 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.<ref name="Chen">doi:10.1210/en.2006-1754</ref>. Due to its unique inhibition, CS-17 can be a popular therapy for many thyroid diseases where the thyroid is overactive.
 ===TSH Agonist===
-[[Image:NAG.png|200 px|left|thumb|Figure 3]]
+[[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 2). 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 3). They stick out from the alpha subunit of TSH to clash with the cell membrane and keep TSH in the active state.
+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.