3fcb

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{{STRUCTURE_3fcb| PDB=3fcb | SCENE= }}
 
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===Crystal structure of transthyretin in complex with iododiflunisal-betaAlaOH===
 
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{{ABSTRACT_PUBMED_19125186}}
 
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==Disease==
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==Crystal structure of transthyretin in complex with iododiflunisal-betaAlaOH==
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[[http://www.uniprot.org/uniprot/TTHY_HUMAN TTHY_HUMAN]] Defects in TTR are the cause of amyloidosis transthyretin-related (AMYL-TTR) [MIM:[http://omim.org/entry/105210 105210]]. A hereditary generalized amyloidosis due to transthyretin amyloid deposition. Protein fibrils can form in different tissues leading to amyloid polyneuropathies, amyloidotic cardiomyopathy, carpal tunnel syndrome, systemic senile amyloidosis. The disease includes leptomeningeal amyloidosis that is characterized by primary involvement of the central nervous system. Neuropathologic examination shows amyloid in the walls of leptomeningeal vessels, in pia arachnoid, and subpial deposits. Some patients also develop vitreous amyloid deposition that leads to visual impairment (oculoleptomeningeal amyloidosis). Clinical features include seizures, stroke-like episodes, dementia, psychomotor deterioration, variable amyloid deposition in the vitreous humor.<ref>PMID:11243784</ref><ref>PMID:15735344</ref><ref>PMID:19167329</ref><ref>PMID:3818577</ref><ref>PMID:3022108</ref><ref>PMID:6651852</ref><ref>PMID:6583672</ref><ref>PMID:3135807</ref><ref>PMID:1517749</ref><ref>PMID:1932142</ref><ref>PMID:7923855</ref><ref>PMID:8382610</ref><ref>PMID:8428915</ref><ref>PMID:9733771</ref><ref>PMID:12403615</ref><ref>PMID:16185074</ref><ref>PMID:16627944</ref><ref>PMID:6487335</ref><ref>PMID:3722385</ref><ref>PMID:2891727</ref><ref>PMID:2161654</ref><ref>PMID:2363717</ref><ref>PMID:1656975</ref><ref>PMID:2046936</ref><ref>PMID:1570831</ref><ref>PMID:1734866</ref><ref>PMID:1520326</ref><ref>PMID:1520336</ref><ref>PMID:1544214</ref><ref>PMID:1351039</ref><ref>PMID:1301926</ref><ref>PMID:1362222</ref><ref>PMID:1436517</ref><ref>PMID:8352764</ref><ref>PMID:8038017</ref><ref>PMID:8257997</ref><ref>PMID:8095302</ref>[:]<ref>PMID:8019560</ref><ref>PMID:8081397</ref><ref>PMID:7914929</ref><ref>PMID:8133316</ref><ref>PMID:7910950</ref><ref>PMID:7655883</ref><ref>PMID:7850982</ref><ref>PMID:8579098</ref><ref>PMID:9066351</ref><ref>PMID:8990019</ref><ref>PMID:9605286</ref><ref>PMID:10036587</ref><ref>PMID:10627135</ref><ref>PMID:10694917</ref><ref>PMID:10211412</ref><ref>PMID:10439117</ref><ref>PMID:10611950</ref><ref>PMID:10071047</ref><ref>PMID:10436378</ref><ref>PMID:10842705</ref><ref>PMID:10842718</ref><ref>PMID:10882995</ref><ref>PMID:11445644</ref><ref>PMID:12557757</ref><ref>PMID:11866053</ref><ref>PMID:12050338</ref><ref>PMID:12771253</ref><ref>PMID:15214015</ref><ref>PMID:15478468</ref><ref>PMID:15217993</ref><ref>PMID:17453626</ref><ref>PMID:17577687</ref><ref>PMID:17503405</ref><ref>PMID:17635579</ref> Defects in TTR are a cause of hyperthyroxinemia dystransthyretinemic euthyroidal (HTDE) [MIM:[http://omim.org/entry/145680 145680]]. It is a condition characterized by elevation of total and free thyroxine in healthy, euthyroid persons without detectable binding protein abnormalities.<ref>PMID:1979335</ref> Defects in TTR are a cause of carpal tunnel syndrome type 1 (CTS1) [MIM:[http://omim.org/entry/115430 115430]]. It is a condition characterized by entrapment of the median nerve within the carpal tunnel. Symptoms include burning pain and paresthesias involving the ventral surface of the hand and fingers which may radiate proximally. Impairment of sensation in the distribution of the median nerve and thenar muscle atrophy may occur. This condition may be associated with repetitive occupational trauma, wrist injuries, amyloid neuropathies, rheumatoid arthritis.<ref>PMID:8309582</ref>
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<StructureSection load='3fcb' size='340' side='right'caption='[[3fcb]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3fcb]] is a 2 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=3FCB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FCB 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]] 1.8&#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=IFB:N-[(2,4-DIFLUORO-4-HYDROXY-5-IODOBIPHENYL-3-YL)CARBONYL]-BETA-ALANINE'>IFB</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=3fcb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fcb OCA], [https://pdbe.org/3fcb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fcb RCSB], [https://www.ebi.ac.uk/pdbsum/3fcb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fcb ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/TTHY_HUMAN TTHY_HUMAN] Defects in TTR are the cause of amyloidosis transthyretin-related (AMYL-TTR) [MIM:[https://omim.org/entry/105210 105210]. A hereditary generalized amyloidosis due to transthyretin amyloid deposition. Protein fibrils can form in different tissues leading to amyloid polyneuropathies, amyloidotic cardiomyopathy, carpal tunnel syndrome, systemic senile amyloidosis. The disease includes leptomeningeal amyloidosis that is characterized by primary involvement of the central nervous system. Neuropathologic examination shows amyloid in the walls of leptomeningeal vessels, in pia arachnoid, and subpial deposits. Some patients also develop vitreous amyloid deposition that leads to visual impairment (oculoleptomeningeal amyloidosis). Clinical features include seizures, stroke-like episodes, dementia, psychomotor deterioration, variable amyloid deposition in the vitreous humor.<ref>PMID:11243784</ref> <ref>PMID:15735344</ref> <ref>PMID:19167329</ref> <ref>PMID:3818577</ref> <ref>PMID:3022108</ref> <ref>PMID:6651852</ref> <ref>PMID:6583672</ref> <ref>PMID:3135807</ref> <ref>PMID:1517749</ref> <ref>PMID:1932142</ref> <ref>PMID:7923855</ref> <ref>PMID:8382610</ref> <ref>PMID:8428915</ref> <ref>PMID:9733771</ref> <ref>PMID:12403615</ref> <ref>PMID:16185074</ref> <ref>PMID:16627944</ref> <ref>PMID:6487335</ref> <ref>PMID:3722385</ref> <ref>PMID:2891727</ref> <ref>PMID:2161654</ref> <ref>PMID:2363717</ref> <ref>PMID:1656975</ref> <ref>PMID:2046936</ref> <ref>PMID:1570831</ref> <ref>PMID:1734866</ref> <ref>PMID:1520326</ref> <ref>PMID:1520336</ref> <ref>PMID:1544214</ref> <ref>PMID:1351039</ref> <ref>PMID:1301926</ref> <ref>PMID:1362222</ref> <ref>PMID:1436517</ref> <ref>PMID:8352764</ref> <ref>PMID:8038017</ref> <ref>PMID:8257997</ref> <ref>PMID:8095302</ref> <ref>PMID:1997217</ref> <ref>PMID:8019560</ref> <ref>PMID:8081397</ref> <ref>PMID:7914929</ref> <ref>PMID:8133316</ref> <ref>PMID:7910950</ref> <ref>PMID:7655883</ref> <ref>PMID:7850982</ref> <ref>PMID:8579098</ref> <ref>PMID:9066351</ref> <ref>PMID:8990019</ref> <ref>PMID:9605286</ref> <ref>PMID:10036587</ref> <ref>PMID:10627135</ref> <ref>PMID:10694917</ref> <ref>PMID:10211412</ref> <ref>PMID:10439117</ref> <ref>PMID:10611950</ref> <ref>PMID:10071047</ref> <ref>PMID:10436378</ref> <ref>PMID:10842705</ref> <ref>PMID:10842718</ref> <ref>PMID:10882995</ref> <ref>PMID:11445644</ref> <ref>PMID:12557757</ref> <ref>PMID:11866053</ref> <ref>PMID:12050338</ref> <ref>PMID:12771253</ref> <ref>PMID:15214015</ref> <ref>PMID:15478468</ref> <ref>PMID:15217993</ref> <ref>PMID:17453626</ref> <ref>PMID:17577687</ref> <ref>PMID:17503405</ref> <ref>PMID:17635579</ref> Defects in TTR are a cause of hyperthyroxinemia dystransthyretinemic euthyroidal (HTDE) [MIM:[https://omim.org/entry/145680 145680]. It is a condition characterized by elevation of total and free thyroxine in healthy, euthyroid persons without detectable binding protein abnormalities.<ref>PMID:1979335</ref> Defects in TTR are a cause of carpal tunnel syndrome type 1 (CTS1) [MIM:[https://omim.org/entry/115430 115430]. It is a condition characterized by entrapment of the median nerve within the carpal tunnel. Symptoms include burning pain and paresthesias involving the ventral surface of the hand and fingers which may radiate proximally. Impairment of sensation in the distribution of the median nerve and thenar muscle atrophy may occur. This condition may be associated with repetitive occupational trauma, wrist injuries, amyloid neuropathies, rheumatoid arthritis.<ref>PMID:8309582</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/TTHY_HUMAN TTHY_HUMAN] Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.<ref>PMID:3714052</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/fc/3fcb_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=3fcb 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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The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis.
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==Function==
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Iodine atoms: a new molecular feature for the design of potent transthyretin fibrillogenesis inhibitors.,Mairal T, Nieto J, Pinto M, Almeida MR, Gales L, Ballesteros A, Barluenga J, Perez JJ, Vazquez JT, Centeno NB, Saraiva MJ, Damas AM, Planas A, Arsequell G, Valencia G PLoS ONE. 2009;4(1):e4124. Epub 2009 Jan 6. PMID:19125186<ref>PMID:19125186</ref>
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[[http://www.uniprot.org/uniprot/TTHY_HUMAN TTHY_HUMAN]] Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.<ref>PMID:3714052</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3fcb]] is a 2 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=3FCB OCA].
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</div>
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<div class="pdbe-citations 3fcb" style="background-color:#fffaf0;"></div>
==See Also==
==See Also==
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*[[Transthyretin|Transthyretin]]
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*[[Transthyretin 3D structures|Transthyretin 3D structures]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:019125186</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Damas, A M.]]
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[[Category: Large Structures]]
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[[Category: Gales, L.]]
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[[Category: Damas AM]]
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[[Category: Amyloid]]
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[[Category: Gales L]]
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[[Category: Hormone binding protein]]
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[[Category: Inhibitor]]
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[[Category: Iodine]]
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[[Category: Polyneuropathy]]
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[[Category: Retinol-binding]]
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[[Category: Secreted]]
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[[Category: Transthyretin]]
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Current revision

Crystal structure of transthyretin in complex with iododiflunisal-betaAlaOH

PDB ID 3fcb

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