3g04

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[[Image:3g04.png|left|200px]]
 
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{{STRUCTURE_3g04| PDB=3g04 | SCENE= }}
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==Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody==
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<StructureSection load='3g04' size='340' side='right'caption='[[3g04]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3g04]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3G04 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3G04 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.55&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3g04 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g04 OCA], [https://pdbe.org/3g04 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3g04 RCSB], [https://www.ebi.ac.uk/pdbsum/3g04 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3g04 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/TSHR_HUMAN TSHR_HUMAN] Note=Defects in TSHR are found in patients affected by hyperthyroidism with different etiologies. Somatic, constitutively activating TSHR mutations and/or constitutively activating G(s)alpha mutations have been identified in toxic thyroid nodules (TTNs) that are the predominant cause of hyperthyroidism in iodine deficient areas. These mutations lead to TSH independent activation of the cAMP cascade resulting in thyroid growth and hormone production. TSHR mutations are found in autonomously functioning thyroid nodules (AFTN), toxic multinodular goiter (TMNG) and hyperfunctioning thyroid adenomas (HTA). TMNG encompasses a spectrum of different clinical entities, ranging from a single hyperfunctioning nodule within an enlarged thyroid, to multiple hyperfunctioning areas scattered throughout the gland. HTA are discrete encapsulated neoplasms characterized by TSH-independent autonomous growth, hypersecretion of thyroid hormones, and TSH suppression. Defects in TSHR are also a cause of thyroid neoplasms (papillary and follicular cancers).<ref>PMID:11887032</ref> <ref>PMID:12593721</ref> <ref>PMID:12930595</ref> Note=Autoantibodies against TSHR are directly responsible for the pathogenesis and hyperthyroidism of Graves disease. Antibody interaction with TSHR results in an uncontrolled receptor stimulation.<ref>PMID:11887032</ref> <ref>PMID:12593721</ref> <ref>PMID:12930595</ref> Defects in TSHR are the cause of congenital hypothyroidism non-goitrous type 1 (CHNG1) [MIM:[https://omim.org/entry/275200 275200]; also known as congenital hypothyroidism due to TSH resistance. CHNG1 is a non-autoimmune condition characterized by resistance to thyroid-stimulating hormone (TSH) leading to increased levels of plasma TSH and low levels of thyroid hormone. CHNG1 presents variable severity depending on the completeness of the defect. Most patients are euthyroid and asymptomatic, with a normal sized thyroid gland. Only a subset of patients develop hypothyroidism and present a hypoplastic thyroid gland.<ref>PMID:11887032</ref> <ref>PMID:12593721</ref> <ref>PMID:12930595</ref> <ref>PMID:7528344</ref> <ref>PMID:8954020</ref> <ref>PMID:9100579</ref> <ref>PMID:9329388</ref> <ref>PMID:9185526</ref> <ref>PMID:10720030</ref> <ref>PMID:11095460</ref> <ref>PMID:11442002</ref> <ref>PMID:12050212</ref> <ref>PMID:14725684</ref> <ref>PMID:15531543</ref> Defects in TSHR are the cause of familial gestational hyperthyroidism (HTFG) [MIM:[https://omim.org/entry/603373 603373]. HTFG is a condition characterized by abnormally high levels of serum thyroid hormones occurring during early pregnancy.<ref>PMID:11887032</ref> <ref>PMID:12593721</ref> <ref>PMID:12930595</ref> <ref>PMID:9854118</ref> Defects in TSHR are the cause of hyperthyroidism non-autoimmune (HTNA) [MIM:[https://omim.org/entry/609152 609152]. It is a condition characterized by abnormally high levels of serum thyroid hormones, thyroid hyperplasia, goiter and lack of anti-thyroid antibodies. Typical features of Graves disease such as exophthalmia, myxedema, antibodies anti-TSH receptor and lymphocytic infiltration of the thyroid gland are absent.<ref>PMID:11887032</ref> <ref>PMID:12593721</ref> <ref>PMID:12930595</ref> <ref>PMID:7920658</ref> <ref>PMID:7800007</ref> <ref>PMID:8636266</ref> <ref>PMID:8964822</ref> <ref>PMID:9360555</ref> <ref>PMID:9398746</ref> <ref>PMID:9349581</ref> <ref>PMID:9589634</ref> <ref>PMID:10199795</ref> <ref>PMID:10852462</ref> <ref>PMID:11127522</ref> <ref>PMID:11081252</ref> <ref>PMID:11201847</ref> <ref>PMID:11517004</ref> <ref>PMID:11549687</ref> <ref>PMID:15163335</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/TSHR_HUMAN TSHR_HUMAN] Receptor for thyrothropin. Plays a central role in controlling thyroid cell metabolism. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Also acts as a receptor for thyrostimulin (GPA2+GPB5).<ref>PMID:12045258</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g0/3g04_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3g04 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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OBJECTIVE: To analyze interactions between the thyroid-stimulating hormone receptor (TSHR) and a thyroid-stimulating human monoclonal autoantibody (M22) at the molecular level. DESIGN: A complex of part of the TSHR extracellular domain (amino acids 1-260; TSHR260) bound to M22 Fab was prepared and purified. Crystals suitable for X-ray diffraction analysis were obtained and the structure solved at 2.55 A resolution. MAIN OUTCOME: TSHR260 comprises of a curved helical tube and M22 Fab clasps its concave surface at 90 degrees to the tube length axis. The interface buried in the complex is large (2,500 A(2)) and an extensive network of ionic, polar, and hydrophobic bonding is involved in the interaction. There is virtually no movement in the atoms of M22 residues on the binding interface compared to unbound M22 consistent with "lock and key" binding. Mutation of residues showing strong interactions in the structure influenced M22 activity, indicating that the binding detail observed in the complex reflects interactions of M22 with intact, functionally active TSHR. The receptor-binding arrangements of the autoantibody are very similar to those reported for follicle-stimulating hormone (FSH) binding to the FSH receptor (amino acids 1-268) and consequently to those of TSH itself. CONCLUSIONS: It is remarkable that the thyroid-stimulating autoantibody shows almost identical receptor-binding features to TSH although the structures and origins of these two ligands are very different. Furthermore, our structure of the TSHR and its complex with M22 provide foundations for developing new strategies to understand and control both glycoprotein hormone receptor activation and the autoimmune response to the TSHR.
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===Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody===
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Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody.,Sanders J, Chirgadze DY, Sanders P, Baker S, Sullivan A, Bhardwaja A, Bolton J, Reeve M, Nakatake N, Evans M, Richards T, Powell M, Miguel RN, Blundell TL, Furmaniak J, Smith BR Thyroid. 2007 May;17(5):395-410. PMID:17542669<ref>PMID:17542669</ref>
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{{ABSTRACT_PUBMED_17542669}}
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==About this Structure==
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<div class="pdbe-citations 3g04" style="background-color:#fffaf0;"></div>
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[[3g04]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3G04 OCA].
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==See Also==
==See Also==
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*[[Hormone|Hormone]]
 
*[[Human Follicle-Stimulating Hormone Complexed with its Receptor|Human Follicle-Stimulating Hormone Complexed with its Receptor]]
*[[Human Follicle-Stimulating Hormone Complexed with its Receptor|Human Follicle-Stimulating Hormone Complexed with its Receptor]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:017542669</ref><ref group="xtra">PMID:012867115</ref><ref group="xtra">PMID:015320966</ref><ref group="xtra">PMID:015650352</ref><ref group="xtra">PMID:017199429</ref><ref group="xtra">PMID:017725428</ref><ref group="xtra">PMID:018606720</ref><references group="xtra"/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Baker, S.]]
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[[Category: Large Structures]]
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[[Category: Bhardwaja, A.]]
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[[Category: Baker S]]
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[[Category: Blundell, T L.]]
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[[Category: Bhardwaja A]]
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[[Category: Bolton, J.]]
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[[Category: Blundell TL]]
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[[Category: Chirgadze, D Y.]]
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[[Category: Bolton J]]
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[[Category: Evans, M.]]
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[[Category: Chirgadze DY]]
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[[Category: Furmaniak, J.]]
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[[Category: Evans M]]
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[[Category: Miguel, R N.]]
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[[Category: Furmaniak J]]
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[[Category: Nakatake, N.]]
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[[Category: Miguel RN]]
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[[Category: Powell, M.]]
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[[Category: Nakatake N]]
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[[Category: Reeve, M.]]
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[[Category: Powell M]]
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[[Category: Richards, T.]]
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[[Category: Reeve M]]
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[[Category: Sanders, J.]]
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[[Category: Richards T]]
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[[Category: Sanders, P.]]
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[[Category: Sanders J]]
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[[Category: Smith, B R.]]
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[[Category: Sanders P]]
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[[Category: Sullivan, A.]]
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[[Category: Smith BR]]
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[[Category: Autoimmunity]]
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[[Category: Sullivan A]]
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[[Category: Gpcr]]
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[[Category: Graves' disease]]
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[[Category: Immune system]]
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[[Category: Receptor-autoantibody complex]]
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[[Category: Thyroid]]
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[[Category: Tsh receptor]]
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Current revision

Crystal structure of the TSH receptor in complex with a thyroid-stimulating autoantibody

PDB ID 3g04

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