2b16

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{{STRUCTURE_2b16| PDB=2b16 | SCENE= }}
 
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===The crystal structure of 2,4-dinitrophenol in complex with the amyloidogenic variant Transthyretin Tyr78Phe===
 
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{{ABSTRACT_PUBMED_16627944}}
 
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==Disease==
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==The crystal structure of 2,4-dinitrophenol in complex with the amyloidogenic variant Transthyretin Tyr78Phe==
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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: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:[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='2b16' size='340' side='right'caption='[[2b16]], [[Resolution|resolution]] 1.75&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2b16]] 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=2B16 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2B16 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]] 1.75&#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=DNF:2,4-DINITROPHENOL'>DNF</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=2b16 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2b16 OCA], [https://pdbe.org/2b16 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2b16 RCSB], [https://www.ebi.ac.uk/pdbsum/2b16 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2b16 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/b1/2b16_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=2b16 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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Systemic deposition of transthyretin (TTR) amyloid fibrils is always observed in familial amyloidotic polyneuropathy, senile systemic amyloidosis and familial amyloidotic cardiomyopathy patients. Destabilization of the molecule leads to a cascade of events which result in fibril formation. The destabilization of a native protein with consequent conformational changes appears to be a common link in several human amyloid diseases. Intensive research has been directed towards finding small molecules that could work as therapeutic agents for the prevention/inhibition of amyloid diseases through stabilization of the native fold of the potentially amyloidogenic protein. This work provides insight into the structural determinants of the highly stabilizing effects of 2,4-dinitrophenol on wild-type TTR. It is also shown that similar interactions are established between this molecule and two highly amyloidogenic TTR variants: TTR L55P and TTR Y78F. In the three crystal complexes, 2,4-dinitrophenol occupies the two hormone-binding sites of the TTR tetramer. As a result of 2,4-dinitrophenol binding, the two dimers in the TTR tetramer become closer, increasing the stability of the protein. The three-dimensional structures now determined allow a comprehensive description of key interactions between transthyretin and 2,4-dinitrophenol, a small compound that holds promise as a template for the design of a therapeutical drug for amyloid diseases.
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==Function==
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The binding of 2,4-dinitrophenol to wild-type and amyloidogenic transthyretin.,Morais-de-Sa E, Neto-Silva RM, Pereira PJ, Saraiva MJ, Damas AM Acta Crystallogr D Biol Crystallogr. 2006 May;62(Pt 5):512-9. Epub 2006, Apr 19. PMID:16627944<ref>PMID:16627944</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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[[2b16]] 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=2B16 OCA].
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</div>
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<div class="pdbe-citations 2b16" 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:016627944</ref><ref group="xtra">PMID:016634633</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: Morais-de-Sa, E.]]
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[[Category: Damas AM]]
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[[Category: Neto-Silva, R M.]]
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[[Category: Morais-de-Sa E]]
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[[Category: Pereira, P J.]]
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[[Category: Neto-Silva RM]]
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[[Category: Saraiva, M J.]]
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[[Category: Pereira PJ]]
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[[Category: 4-dinitrophenol]]
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[[Category: Saraiva MJ]]
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[[Category: Amyloid]]
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[[Category: Tetramer stabilizer]]
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[[Category: Transport protein]]
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[[Category: Transthyretin]]
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Current revision

The crystal structure of 2,4-dinitrophenol in complex with the amyloidogenic variant Transthyretin Tyr78Phe

PDB ID 2b16

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