Sandbox Reserved 1780 - Revision history

Colin Flynn at 20:13, 15 April 2023

Colin Flynn — Sat, 15 Apr 2023 20:13:15 GMT

←Older revision		Revision as of 20:13, 15 April 2023
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	<scene name='95/952708/M22_edited/3'>M22</scene> is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that is produced by patients 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>. Grave's Disease is an autoimmune disease that is a result of hyperthyroidism, where too much TSH is being produced. This disease [https://www.niddk.nih.gov/health-information/endocrine-diseases/graves-disease effects 1 in 100 Americans and especially women or people older than 30 years of age]. The M22 [https://en.wikipedia.org/wiki/Autoantibody autoantibody] activates TSHR by causing a membrane clash with the ECD and the 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, and is a potent activator for intracellular signaling. <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.<ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref> These findings show 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. Here the membrane clashes are demonstrated on TSHR with different agonists attached. CS-17 is orange, TSH is purple, and M22 is blue in the figure. The TSHR protein is green and embedded in the protein.]]		<scene name='95/952708/M22_edited/3'>M22</scene> is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that is produced by patients 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>. Grave's Disease is an autoimmune disease that is a result of hyperthyroidism, where too much TSH is being produced. This disease [https://www.niddk.nih.gov/health-information/endocrine-diseases/graves-disease effects 1 in 100 Americans and especially women or people older than 30 years of age]. The M22 [https://en.wikipedia.org/wiki/Autoantibody autoantibody] activates TSHR by causing a membrane clash with the ECD and the 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, and is a potent activator for intracellular signaling. <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.<ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref> These findings show 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. Here the membrane clashes are demonstrated on TSHR with different agonists attached. CS-17 is orange, TSH is purple, and M22 is blue in the figure. The TSHR protein is green and embedded in the protein.]]
	===CS-17 Inverse Agonist===		===CS-17 Inverse Agonist===
-	<scene name='95/952708/Cs17/1'>CS-17</scene> is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that acts as an inverse agonist for TSHR constitutive activity. <ref name= "Chen et al.">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</ref>. An example of a disease caused by inverse agonists is [https://www.mayoclinic.org/diseasesconditions/hypothyroidism/symptomscauses/syc20350284#:~:text=Hypothyroidism%20happens%20when%20the%20thyroid,symptoms%20in%20its%20early%20stages hypothyroidism]. The most common cause of hypothyroidism is [https://www.mayoclinic.org/diseasesconditions/hypothyroidism/symptomscauses/syc20350284#:~:text=Hypothyroidism%20happens%20when%20the%20thyroid,symptoms%20in%20its%20early%20stages Hashimoto’s disease]. Without enough TSH to bind TSHR, the pathway remains inactive and thus metabolic processes are inhibited in this pathway. CS-17 interacts with the ECD of the TSHR protein on the convex side ~~GREEN LINK~~ of the LRRD, suppressing TSHR function by keeping the receptor in the inactive state (Figure 3). Clash of bound CS-17 with the cell membrane locks TSHR in the inactive form. This type of inhibition is uncommon and is a promising mechanism for future drug design and research to combat hypothyroidism.<ref name="Chen et al.">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</ref>.	+	<scene name='95/952708/Cs17/1'>CS-17</scene> is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that acts as an inverse agonist for TSHR constitutive activity. <ref name= "Chen et al.">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</ref>. An example of a disease caused by inverse agonists is [https://www.mayoclinic.org/diseasesconditions/hypothyroidism/symptomscauses/syc20350284#:~:text=Hypothyroidism%20happens%20when%20the%20thyroid,symptoms%20in%20its%20early%20stages hypothyroidism]. The most common cause of hypothyroidism is [https://www.mayoclinic.org/diseasesconditions/hypothyroidism/symptomscauses/syc20350284#:~:text=Hypothyroidism%20happens%20when%20the%20thyroid,symptoms%20in%20its%20early%20stages Hashimoto’s disease]. Without enough TSH to bind TSHR, the pathway remains inactive and thus metabolic processes are inhibited in this pathway. CS-17 interacts with the ECD of the TSHR protein on the
		+	<scene name='95/952708/Cs17/2'>convex side</scene> of the LRRD, suppressing TSHR function by keeping the receptor in the inactive state (Figure 3). Clash of bound CS-17 with the cell membrane locks TSHR in the inactive form. This type of inhibition is uncommon and is a promising mechanism for future drug design and research to combat hypothyroidism.<ref name="Chen et al.">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</ref>.

Colin Flynn at 20:07, 15 April 2023

Colin Flynn — Sat, 15 Apr 2023 20:07:25 GMT

←Older revision		Revision as of 20:07, 15 April 2023
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	<scene name='95/952708/M22_edited/3'>M22</scene> is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that is produced by patients 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>. Grave's Disease is an autoimmune disease that is a result of hyperthyroidism, where too much TSH is being produced. This disease [https://www.niddk.nih.gov/health-information/endocrine-diseases/graves-disease effects 1 in 100 Americans and especially women or people older than 30 years of age]. The M22 [https://en.wikipedia.org/wiki/Autoantibody autoantibody] activates TSHR by causing a membrane clash with the ECD and the 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, and is a potent activator for intracellular signaling. <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.<ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref> These findings show 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. Here the membrane clashes are demonstrated on TSHR with different agonists attached. CS-17 is orange, TSH is purple, and M22 is blue in the figure. The TSHR protein is green and embedded in the protein.]]		<scene name='95/952708/M22_edited/3'>M22</scene> is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that is produced by patients 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>. Grave's Disease is an autoimmune disease that is a result of hyperthyroidism, where too much TSH is being produced. This disease [https://www.niddk.nih.gov/health-information/endocrine-diseases/graves-disease effects 1 in 100 Americans and especially women or people older than 30 years of age]. The M22 [https://en.wikipedia.org/wiki/Autoantibody autoantibody] activates TSHR by causing a membrane clash with the ECD and the 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, and is a potent activator for intracellular signaling. <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.<ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref> These findings show 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. Here the membrane clashes are demonstrated on TSHR with different agonists attached. CS-17 is orange, TSH is purple, and M22 is blue in the figure. The TSHR protein is green and embedded in the protein.]]
	===CS-17 Inverse Agonist===		===CS-17 Inverse Agonist===
-	<scene name='95/~~952707~~/Cs17/3'>CS-17</scene> ~~(GREEN LINK add TMD and 1 color for CS-17)~~ is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that acts as an inverse agonist for TSHR constitutive activity. <ref name= "Chen et al.">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</ref>. An example of a disease caused by inverse agonists is [https://www.mayoclinic.org/diseasesconditions/hypothyroidism/symptomscauses/syc20350284#:~:text=Hypothyroidism%20happens%20when%20the%20thyroid,symptoms%20in%20its%20early%20stages hypothyroidism]. The most common cause of hypothyroidism is [https://www.mayoclinic.org/diseasesconditions/hypothyroidism/symptomscauses/syc20350284#:~:text=Hypothyroidism%20happens%20when%20the%20thyroid,symptoms%20in%20its%20early%20stages Hashimoto’s disease]. Without enough TSH to bind TSHR, the pathway remains inactive and thus metabolic processes are inhibited in this pathway. CS-17 interacts with the ECD of the TSHR protein on the convex side GREEN LINK of the LRRD, suppressing TSHR function by keeping the receptor in the inactive state (Figure 3). Clash of bound CS-17 with the cell membrane locks TSHR in the inactive form. This type of inhibition is uncommon and is a promising mechanism for future drug design and research to combat hypothyroidism.<ref name="Chen et al.">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</ref>.	+	<scene name='95/952708/Cs17/1'>CS-17</scene> is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that acts as an inverse agonist for TSHR constitutive activity. <ref name= "Chen et al.">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</ref>. An example of a disease caused by inverse agonists is [https://www.mayoclinic.org/diseasesconditions/hypothyroidism/symptomscauses/syc20350284#:~:text=Hypothyroidism%20happens%20when%20the%20thyroid,symptoms%20in%20its%20early%20stages hypothyroidism]. The most common cause of hypothyroidism is [https://www.mayoclinic.org/diseasesconditions/hypothyroidism/symptomscauses/syc20350284#:~:text=Hypothyroidism%20happens%20when%20the%20thyroid,symptoms%20in%20its%20early%20stages Hashimoto’s disease]. Without enough TSH to bind TSHR, the pathway remains inactive and thus metabolic processes are inhibited in this pathway. CS-17 interacts with the ECD of the TSHR protein on the convex side GREEN LINK of the LRRD, suppressing TSHR function by keeping the receptor in the inactive state (Figure 3). Clash of bound CS-17 with the cell membrane locks TSHR in the inactive form. This type of inhibition is uncommon and is a promising mechanism for future drug design and research to combat hypothyroidism.<ref name="Chen et al.">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</ref>.

Colin Flynn at 19:59, 15 April 2023

Colin Flynn — Sat, 15 Apr 2023 19:59:59 GMT

←Older revision		Revision as of 19:59, 15 April 2023
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	=== Active and Inactive Form ===		=== Active and Inactive Form ===
	[[Image:Finalmorphpic2.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).]]		[[Image:Finalmorphpic2.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 dynamic equilibrium between two states: active and inactive (Figure 2~~) (GREEN LINK~~). TSH ~~(GREEN LINK)~~ will bind and keep the active state in the up position as a result of clashes between bound TSH and the cell membrane.<ref name="Faust" />. ~~Glycosylations~~ of an ~~Asn52~~ residue cause this clash ~~(GREEN LINK)~~ on the <scene name='95/952707/Tsh_7t9i/1'>α-subunit of TSH</scene>.	+	The TSHR protein exists in dynamic equilibrium between two states: active and inactive (Figure 2). <scene name='95/952708/Tsh_7t9i/2'>TSH</scene> will bind and keep the active state in the up position as a result of clashes between bound TSH and the cell membrane.<ref name="Faust" />. <scene name='95/952708/Tsh_7t9i/4'>Glycolysations of an ASN52 residue</scene> cause this clash on the <scene name='95/952707/Tsh_7t9i/1'>α-subunit of TSH</scene>.

	== TSHR Agonists and Antagonists ==		== TSHR Agonists and Antagonists ==

Colin Flynn at 19:25, 15 April 2023

Colin Flynn — Sat, 15 Apr 2023 19:25:59 GMT

←Older revision		Revision as of 19:25, 15 April 2023
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	=== Active and Inactive Form ===		=== Active and Inactive Form ===
	[[Image:Finalmorphpic2.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).]]		[[Image:Finalmorphpic2.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) (GREEN LINK ?). ~~The <scene name='95/952708/Tshr_chainr/4'>TSHR active form</scene> (GREEN LINK take away extra molecules) exists in dynamic equilibrium where <scene name='95/952708/Tsh_7t9i/1'>~~TSH~~</scene>~~ (GREEN LINK ~~make TSH one color~~) ~~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" />. Glycosylations of ~~the~~ Asn52 residue cause this clash (GREEN LINK) on the <scene name='95/952707/Tsh_7t9i/1'>α-subunit of TSH</scene>~~. The addition of N-acetyl glucosamine modifications creates steric clashes between TSH and the cell membrane, keeping TSHR in the active state~~.	+	The TSHR protein exists in dynamic equilibrium between two states: active and inactive (Figure 2) (GREEN LINK). TSH (GREEN LINK) will bind and keep the active state in the up position as a result of clashes between bound TSH and the cell membrane.<ref name="Faust" />. Glycosylations of an Asn52 residue cause this clash (GREEN LINK) on the <scene name='95/952707/Tsh_7t9i/1'>α-subunit of TSH</scene>.

	== 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.<ref name="Miguel"> doi:10.1677/JME-08-0152</ref>.	+	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 leading to disease.<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 is produced by patients 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>. Grave's Disease is an autoimmune disease that is a result of hyperthyroidism, where too much TSH is being produced. This disease [https://www.niddk.nih.gov/health-information/endocrine-diseases/graves-disease effects 1 in 100 Americans and especially women or people older than 30 years of age]. 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, and is a potent activator for intracellular signaling. <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. Here the membrane clashes are demonstrated on TSHR with different agonists attached. CS-17 is orange, TSH is purple, and M22 is blue in the figure. The TSHR protein is green and embedded in the protein.]]	+	<scene name='95/952708/M22_edited/3'>M22</scene> is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that is produced by patients 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>. Grave's Disease is an autoimmune disease that is a result of hyperthyroidism, where too much TSH is being produced. This disease [https://www.niddk.nih.gov/health-information/endocrine-diseases/graves-disease effects 1 in 100 Americans and especially women or people older than 30 years of age]. The M22 [https://en.wikipedia.org/wiki/Autoantibody autoantibody] activates TSHR by causing a membrane clash with the ECD and the 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, and is a potent activator for intracellular signaling. <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.<ref name="Faust"> DOI:10.1038/s41586-022-05159-1</ref> These findings show 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. Here the membrane clashes are demonstrated on TSHR with different agonists attached. CS-17 is orange, TSH is purple, and M22 is blue in the figure. The TSHR protein is green and embedded in the protein.]]
	===CS-17 Inverse Agonist===		===CS-17 Inverse Agonist===
	<scene name='95/952707/Cs17/3'>CS-17</scene> (GREEN LINK add TMD and 1 color for CS-17) is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that acts as an inverse agonist for TSHR constitutive activity. <ref name= "Chen et al.">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</ref>. An example of a disease caused by inverse agonists is [https://www.mayoclinic.org/diseasesconditions/hypothyroidism/symptomscauses/syc20350284#:~:text=Hypothyroidism%20happens%20when%20the%20thyroid,symptoms%20in%20its%20early%20stages hypothyroidism]. The most common cause of hypothyroidism is [https://www.mayoclinic.org/diseasesconditions/hypothyroidism/symptomscauses/syc20350284#:~:text=Hypothyroidism%20happens%20when%20the%20thyroid,symptoms%20in%20its%20early%20stages Hashimoto’s disease]. Without enough TSH to bind TSHR, the pathway remains inactive and thus metabolic processes are inhibited in this pathway. CS-17 interacts with the ECD of the TSHR protein on the convex side GREEN LINK of the LRRD, suppressing TSHR function by keeping the receptor in the inactive state (Figure 3). Clash of bound CS-17 with the cell membrane locks TSHR in the inactive form. This type of inhibition is uncommon and is a promising mechanism for future drug design and research to combat hypothyroidism.<ref name="Chen et al.">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</ref>.		<scene name='95/952707/Cs17/3'>CS-17</scene> (GREEN LINK add TMD and 1 color for CS-17) is a [https://en.wikipedia.org/wiki/Monoclonal_antibody monoclonal antibody] that acts as an inverse agonist for TSHR constitutive activity. <ref name= "Chen et al.">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</ref>. An example of a disease caused by inverse agonists is [https://www.mayoclinic.org/diseasesconditions/hypothyroidism/symptomscauses/syc20350284#:~:text=Hypothyroidism%20happens%20when%20the%20thyroid,symptoms%20in%20its%20early%20stages hypothyroidism]. The most common cause of hypothyroidism is [https://www.mayoclinic.org/diseasesconditions/hypothyroidism/symptomscauses/syc20350284#:~:text=Hypothyroidism%20happens%20when%20the%20thyroid,symptoms%20in%20its%20early%20stages Hashimoto’s disease]. Without enough TSH to bind TSHR, the pathway remains inactive and thus metabolic processes are inhibited in this pathway. CS-17 interacts with the ECD of the TSHR protein on the convex side GREEN LINK of the LRRD, suppressing TSHR function by keeping the receptor in the inactive state (Figure 3). Clash of bound CS-17 with the cell membrane locks TSHR in the inactive form. This type of inhibition is uncommon and is a promising mechanism for future drug design and research to combat hypothyroidism.<ref name="Chen et al.">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</ref>.

Colin Flynn at 23:03, 13 April 2023

Colin Flynn — Thu, 13 Apr 2023 23:03:29 GMT

←Older revision		Revision as of 23:03, 13 April 2023
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-	<scene name='95/952708/Sdfad/1'>TextToBeDisplayed</scene>

Colin Flynn at 22:58, 13 April 2023

Colin Flynn — Thu, 13 Apr 2023 22:58:10 GMT

←Older revision	Revision as of 22:58, 13 April 2023
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-	+	<scene name='95/952708/Sdfad/1'>TextToBeDisplayed</scene>

Colin Flynn at 22:53, 13 April 2023

Colin Flynn — Thu, 13 Apr 2023 22:53:31 GMT

←Older revision		Revision as of 22:53, 13 April 2023
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	=== Active and Inactive Form ===		=== Active and Inactive Form ===
-	[[Image:~~Finalmorphpic~~.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).]]	+	[[Image:Finalmorphpic2.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) (GREEN LINK ?). The <scene name='95/952708/Tshr_chainr/4'>TSHR active form</scene> (GREEN LINK take away extra molecules) exists in dynamic equilibrium where <scene name='95/952708/Tsh_7t9i/1'>TSH</scene> (GREEN LINK make TSH one color) 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" />. Glycosylations of the Asn52 residue cause this clash (GREEN LINK) on the <scene name='95/952707/Tsh_7t9i/1'>α-subunit of TSH</scene>. The addition of N-acetyl glucosamine modifications creates steric clashes between TSH and the cell membrane, keeping TSHR in the active state.		The TSHR protein exists in two states: active and inactive (Figure 2) (GREEN LINK ?). The <scene name='95/952708/Tshr_chainr/4'>TSHR active form</scene> (GREEN LINK take away extra molecules) exists in dynamic equilibrium where <scene name='95/952708/Tsh_7t9i/1'>TSH</scene> (GREEN LINK make TSH one color) 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" />. Glycosylations of the Asn52 residue cause this clash (GREEN LINK) on the <scene name='95/952707/Tsh_7t9i/1'>α-subunit of TSH</scene>. The addition of N-acetyl glucosamine modifications creates steric clashes between TSH and the cell membrane, keeping TSHR in the active state.

Colin Flynn at 22:48, 13 April 2023

Colin Flynn — Thu, 13 Apr 2023 22:48:28 GMT

←Older revision		Revision as of 22:48, 13 April 2023
Line 4:		Line 4:

	=== Active and Inactive Form ===		=== 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).]]	+	[[Image:Finalmorphpic.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) (GREEN LINK ?). The <scene name='95/952708/Tshr_chainr/4'>TSHR active form</scene> (GREEN LINK take away extra molecules) exists in dynamic equilibrium where <scene name='95/952708/Tsh_7t9i/1'>TSH</scene> (GREEN LINK make TSH one color) 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" />. Glycosylations of the Asn52 residue cause this clash (GREEN LINK) on the <scene name='95/952707/Tsh_7t9i/1'>α-subunit of TSH</scene>. The addition of N-acetyl glucosamine modifications creates steric clashes between TSH and the cell membrane, keeping TSHR in the active state.		The TSHR protein exists in two states: active and inactive (Figure 2) (GREEN LINK ?). The <scene name='95/952708/Tshr_chainr/4'>TSHR active form</scene> (GREEN LINK take away extra molecules) exists in dynamic equilibrium where <scene name='95/952708/Tsh_7t9i/1'>TSH</scene> (GREEN LINK make TSH one color) 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" />. Glycosylations of the Asn52 residue cause this clash (GREEN LINK) on the <scene name='95/952707/Tsh_7t9i/1'>α-subunit of TSH</scene>. The addition of N-acetyl glucosamine modifications creates steric clashes between TSH and the cell membrane, keeping TSHR in the active state.

Colin Flynn at 22:30, 13 April 2023

Colin Flynn — Thu, 13 Apr 2023 22:30:55 GMT

←Older revision		Revision as of 22:30, 13 April 2023
Line 17:		Line 17:


-	~~[[Image:Morph3.gif\|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).]]~~	+

Colin Flynn at 22:30, 13 April 2023

Colin Flynn — Thu, 13 Apr 2023 22:30:29 GMT

←Older revision		Revision as of 22:30, 13 April 2023
Line 17:		Line 17:


-	[Image:Morph3.gif]	+	[[Image:Morph3.gif\|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).]]