Sandbox Reserved 1791: Difference between revisions

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[https://my.clevelandclinic.org/health/body/22971-antibodies Antibodies] are an important part of the thyroid response. These proteins are made in an immune system response to get rid of unwanted antigens in the body. [https://www.btf-thyroid.org/thyroid-antibodies-explained Thyroid antibodies] are made when the body attacks the thyroid tissues. These antibodies are made to mimic [https://my.clevelandclinic.org/health/articles/23524-thyroid-stimulating-hormone-tsh-levels TSH (Thyroid Stimulating Hormone)]. TSH is released from the pituitary gland to bind to TSHR and stimulate the thyroid to make T3 and T4 hormones to regulate the metabolism. These thyroid antibodies bind to the concave surface of the LRD.

=== M22 ===

M22 is an activating antibody for [https://en.wikipedia.org/wiki/Thyrotropin_receptor TSHR]. This antibody mimics [https://my.clevelandclinic.org/health/articles/23524-thyroid-stimulating-hormone-tsh-levels TSH] to activate the thyroid gland to produce [https://www.healthyandnaturalworld.com/t3-t4-thyroid-hormones/ T3 and T4 hormones]. M22 makes a stronger interaction with TSHR than TSH does due to a larger number of ~~hydrogen bonds and salt bridges~~. This interaction is key for understanding why M22 activates TSHR and does not release TSHR to go into the inactive state even when T3 and T4 levels are high<ref name="M22"> DOI 10.1677/JME-08-0152</ref>.

M22 is an activating antibody for [https://en.wikipedia.org/wiki/Thyrotropin_receptor TSHR]. This antibody mimics [https://my.clevelandclinic.org/health/articles/23524-thyroid-stimulating-hormone-tsh-levels TSH] to activate the thyroid gland to produce [https://www.healthyandnaturalworld.com/t3-t4-thyroid-hormones/ T3 and T4 hormones]. M22 makes a stronger interaction with TSHR than TSH does due to a larger number of interactions with the polar residues of the LRRD. This interaction is key for understanding why M22 activates TSHR and does not release TSHR to go into the inactive state even when T3 and T4 levels are high<ref name="M22"> DOI 10.1677/JME-08-0152</ref>.

=== K1 ===

[https://www.creativebiolabs.net/Anti-TSHR-Recombinant-Antibody-clone-K1-70-24911.htm K1] is an inhibitory antibody. This antibody mimics [[https://my.clevelandclinic.org/health/articles/23524-thyroid-stimulating-hormone-tsh-levels TSH] and blocks it from binding. When K1 is bound it does not allow TSHR to be in the active state like TSH and M22 do to produce T3 and T4 hormones.

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|}

== Specific Residues and Interactions==

On the concave surface of the LRRD two <scene name='95/952719/Specific_residues/6'>lysine residues</scene> are the main contributors to the binding of the antibodies. The concave structure of the binding pocket allows a <scene name='95/952719/Lock_and_key/8'>tight interaction</scene> with antibodies. Specifically, <scene name='95/952719/K---e_interaction/8'>LYS 58</scene> interacts with Glu 118 and <scene name='95/952719/K---d_interaction/9'>LYS 209</scene> interacts with Asp 111 on K1 and M22 antibodies to make a [https://www.nature.com/articles/s41598-018-31935-z salt bridge interaction]~~. Specifically, the two residues make an ionic interaction~~. The interaction is not close enough to make a hydrogen bond. Instead, the interaction between the Lys residues with the Asp or Glu residues is a salt bridge interaction~~. This~~ is ~~the main bond that holds these two molecules together~~. When in the inactive form, LYS 209 ~~does not interact with any residue~~ but LYS 58 ~~has~~ interaction with Glu 118 ~~and this interaction pulls the molecule into the bent position~~. ~~The~~ salt bridge ~~interaction between Lys and Glu is very~~ specific~~. Lys was mutated with~~ Arg ~~and was expected to make the same salt bride interaction with Glu, however it make~~ a ~~completely~~ different interaction. This new interaction favors a gain of function towards [https://my.clevelandclinic.org/health/articles/22489-human-chorionic-gonadotropin hCG] <ref name="Guillaume">Smits G, Govaerts C, Nubourgh I, Pardo L, Vassart G, Costagliola S. Lysine 183 and glutamic acid 157 of the TSH receptor: two interacting residues with a key role in determining specificity toward TSH and human CG. Mol Endocrinol. 2002 Apr;16(4):722-35. doi: 10.1210/mend.16.4.0815. PMID: 11923469. [DOI: 10.1210/mend.16.4.0815 https://pubmed.ncbi.nlm.nih.gov/11923469/]</ref>.

On the concave surface of the LRRD two <scene name='95/952719/Specific_residues/6'>lysine residues</scene> are the main contributors to the binding of the antibodies. The concave structure of the binding pocket allows a <scene name='95/952719/Lock_and_key/8'>tight interaction</scene> with antibodies. Specifically, <scene name='95/952719/K---e_interaction/8'>LYS 58</scene> interacts with Glu 118 and <scene name='95/952719/K---d_interaction/9'>LYS 209</scene> interacts with Asp 111 on K1 and M22 antibodies to make a [https://www.nature.com/articles/s41598-018-31935-z salt bridge interaction]. The interaction is not close enough to make a hydrogen bond. Instead, the interaction between the Lys residues with the Asp or Glu residues is a [https://www.nature.com/articles/s41598-018-31935-z salt bridge interaction] because the distance between the residues is greater than 2Å. When in the inactive form, LYS 209 interaction is absent but LYS 58 interaction with Glu 118 is present. These salt bridge interactions are highly specific as mutation of Lys209 to Arg induced a different interaction. This new interaction favors a gain of function towards [https://my.clevelandclinic.org/health/articles/22489-human-chorionic-gonadotropin hCG] <ref name="Guillaume">Smits G, Govaerts C, Nubourgh I, Pardo L, Vassart G, Costagliola S. Lysine 183 and glutamic acid 157 of the TSH receptor: two interacting residues with a key role in determining specificity toward TSH and human CG. Mol Endocrinol. 2002 Apr;16(4):722-35. doi: 10.1210/mend.16.4.0815. PMID: 11923469. [DOI: 10.1210/mend.16.4.0815 https://pubmed.ncbi.nlm.nih.gov/11923469/]</ref>.

== Biological Relevance ==

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@@ Line 19: / Line 19: @@
 [https://my.clevelandclinic.org/health/body/22971-antibodies Antibodies] are an important part of the thyroid response. These proteins are made in an immune system response to get rid of unwanted antigens in the body. [https://www.btf-thyroid.org/thyroid-antibodies-explained Thyroid antibodies] are made when the body attacks the thyroid tissues. These antibodies are made to mimic [https://my.clevelandclinic.org/health/articles/23524-thyroid-stimulating-hormone-tsh-levels TSH (Thyroid Stimulating Hormone)]. TSH is released from the pituitary gland to bind to TSHR and stimulate the thyroid to make T3 and T4 hormones to regulate the metabolism. These thyroid antibodies bind to the concave surface of the LRD.
 === M22 ===
-M22 is an activating antibody for [https://en.wikipedia.org/wiki/Thyrotropin_receptor TSHR]. This antibody mimics [https://my.clevelandclinic.org/health/articles/23524-thyroid-stimulating-hormone-tsh-levels TSH] to activate the thyroid gland to produce [https://www.healthyandnaturalworld.com/t3-t4-thyroid-hormones/ T3 and T4 hormones]. M22 makes a stronger interaction with TSHR than TSH does due to a larger number of hydrogen bonds and salt bridges. This interaction is key for understanding why M22 activates TSHR and does not release TSHR to go into the inactive state even when T3 and T4 levels are high<ref name="M22"> DOI 10.1677/JME-08-0152</ref>.
+M22 is an activating antibody for [https://en.wikipedia.org/wiki/Thyrotropin_receptor TSHR]. This antibody mimics [https://my.clevelandclinic.org/health/articles/23524-thyroid-stimulating-hormone-tsh-levels TSH] to activate the thyroid gland to produce [https://www.healthyandnaturalworld.com/t3-t4-thyroid-hormones/ T3 and T4 hormones]. M22 makes a stronger interaction with TSHR than TSH does due to a larger number of interactions with the polar residues of the LRRD. This interaction is key for understanding why M22 activates TSHR and does not release TSHR to go into the inactive state even when T3 and T4 levels are high<ref name="M22"> DOI 10.1677/JME-08-0152</ref>.
 === K1 ===
 [https://www.creativebiolabs.net/Anti-TSHR-Recombinant-Antibody-clone-K1-70-24911.htm K1] is an inhibitory antibody. This antibody mimics [[https://my.clevelandclinic.org/health/articles/23524-thyroid-stimulating-hormone-tsh-levels TSH] and blocks it from binding. When K1 is bound it does not allow TSHR to be in the active state like TSH and M22 do to produce T3 and T4 hormones.
@@ Line 32: / Line 32: @@
 |}
 == Specific Residues and Interactions==
-On the concave surface of the LRRD two <scene name='95/952719/Specific_residues/6'>lysine residues</scene> are the main contributors to the binding of the antibodies. The concave structure of the binding pocket allows a <scene name='95/952719/Lock_and_key/8'>tight interaction</scene> with antibodies. Specifically, <scene name='95/952719/K---e_interaction/8'>LYS 58</scene> interacts with Glu 118 and <scene name='95/952719/K---d_interaction/9'>LYS 209</scene> interacts with Asp 111 on K1 and M22 antibodies to make a [https://www.nature.com/articles/s41598-018-31935-z salt bridge interaction]. Specifically, the two residues make an ionic interaction. The interaction is not close enough to make a hydrogen bond. Instead, the interaction between the Lys residues with the Asp or Glu residues is a salt bridge interaction. This is the main bond that holds these two molecules together. When in the inactive form, LYS 209 does not interact with any residue but LYS 58 has interaction with Glu 118 and this interaction pulls the molecule into the bent position. The salt bridge interaction between Lys and Glu is very specific. Lys was mutated with Arg and was expected to make the same salt bride interaction with Glu, however it make a completely different interaction. This new interaction favors a gain of function towards [https://my.clevelandclinic.org/health/articles/22489-human-chorionic-gonadotropin hCG] <ref name="Guillaume">Smits G, Govaerts C, Nubourgh I, Pardo L, Vassart G, Costagliola S. Lysine 183 and glutamic acid 157 of the TSH receptor: two interacting residues with a key role in determining specificity toward TSH and human CG. Mol Endocrinol. 2002 Apr;16(4):722-35. doi: 10.1210/mend.16.4.0815. PMID: 11923469. [DOI: 10.1210/mend.16.4.0815 https://pubmed.ncbi.nlm.nih.gov/11923469/]</ref>.
+On the concave surface of the LRRD two <scene name='95/952719/Specific_residues/6'>lysine residues</scene> are the main contributors to the binding of the antibodies. The concave structure of the binding pocket allows a <scene name='95/952719/Lock_and_key/8'>tight interaction</scene> with antibodies. Specifically, <scene name='95/952719/K---e_interaction/8'>LYS 58</scene> interacts with Glu 118 and <scene name='95/952719/K---d_interaction/9'>LYS 209</scene> interacts with Asp 111 on K1 and M22 antibodies to make a [https://www.nature.com/articles/s41598-018-31935-z salt bridge interaction]. The interaction is not close enough to make a hydrogen bond. Instead, the interaction between the Lys residues with the Asp or Glu residues is a [https://www.nature.com/articles/s41598-018-31935-z salt bridge interaction] because the distance between the residues is greater than 2Å. When in the inactive form, LYS 209 interaction is absent but LYS 58 interaction with Glu 118 is present. These salt bridge interactions are highly specific as mutation of Lys209 to Arg induced a different interaction. This new interaction favors a gain of function towards [https://my.clevelandclinic.org/health/articles/22489-human-chorionic-gonadotropin hCG] <ref name="Guillaume">Smits G, Govaerts C, Nubourgh I, Pardo L, Vassart G, Costagliola S. Lysine 183 and glutamic acid 157 of the TSH receptor: two interacting residues with a key role in determining specificity toward TSH and human CG. Mol Endocrinol. 2002 Apr;16(4):722-35. doi: 10.1210/mend.16.4.0815. PMID: 11923469. [DOI: 10.1210/mend.16.4.0815 https://pubmed.ncbi.nlm.nih.gov/11923469/]</ref>.
 == Biological Relevance ==