6grp

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==Crystal Structure Of Human Transthyretin in complex with 3,5,6-trichloro-2-pyridinol (TC2P)==
==Crystal Structure Of Human Transthyretin in complex with 3,5,6-trichloro-2-pyridinol (TC2P)==
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<StructureSection load='6grp' size='340' side='right' caption='[[6grp]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
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<StructureSection load='6grp' size='340' side='right'caption='[[6grp]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6grp]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GRP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GRP FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6grp]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GRP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GRP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F4Z:3,5,6-trichloro-2-pyridinol'>F4Z</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=F4Z:3,5,6-trichloro-2-pyridinol'>F4Z</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TTR, PALB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6grp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6grp OCA], [http://pdbe.org/6grp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6grp RCSB], [http://www.ebi.ac.uk/pdbsum/6grp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6grp ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6grp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6grp OCA], [http://pdbe.org/6grp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6grp RCSB], [http://www.ebi.ac.uk/pdbsum/6grp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6grp ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Thyroid disruption by xenobiotics is associated with a broad spectrum of severe adverse outcomes. One possible molecular target of thyroid hormone disrupting chemicals (THDCs) is transthyretin (TTR), a thyroid hormone transporter in vertebrates. To better understand the interactions between TTR and THDCs, we determined the crystallographic structures of human TTR in complex with perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and 2,2',4,4'-tetrahydroxybenzophenone (BP2). The molecular interactions between the ligands and TTR were further characterized using molecular dynamics simulations. A structure-based virtual screening (VS) protocol was developed with the intention of providing an efficient tool for the discovery of novel TTR binders from the Tox21 inventory. Among the 192 predicted binders, twelve representatives were selected and their TTR binding affinities were studied with isothermal titration calorimetry, of which seven compounds had binding affinities between 0.26-100 muM. To elucidate structural details in their binding to TTR, crystal structures were determined of TTR in complex with four of the identified compounds including 2,6-dinitro-p-cresol, bisphenol S, clonixin and triclopyr. The compounds were found to bind in the TTR hormone binding sites as predicted. Our results show that the developed VS protocol is able to successfully identify potential THDCs and we suggest that it can be used to propose THDCs for future toxicological evaluations.
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Thyroid-disrupting chemicals (TDCs) are xenobiotics that can interfere with the endocrine system and cause adverse effects in organisms and their offspring. TDCs affect both the thyroid gland and regulatory enzymes associated with thyroid hormone homeostasis. Transthyretin (TTR) is found in serum and cerebrospinal fluid of vertebrates, where it transports thyroid hormones. Here we explored the interspecies variation in TDC binding to human and fish TTR (exemplified by Gilthead seabream (Sparus aurata)). The in vitro binding experiments showed that TDCs bind with equal or weaker affinity to seabream TTR than to the human TTR, particular, the polar TDCs (&gt;500-fold lower affinity). Crystal structures of seabream TTR-TDC complexes revealed that all TDCs bound at the thyroid binding sites. However, amino acid substitution of Ser117 in human TTR to Thr117 in seabream prevented polar TDCs from binding deep in the hormone binding cavity, which explains their low affinity to seabream TTR. Molecular dynamics and in silico alanine scanning simulation also suggested that the protein backbone of seabream TTR is more rigid than the human one and that Thr117 provides fewer electrostatic contributions than Ser117 to ligand bindings. This provides an explanation for the weaker affinities of the ligands that rely on electrostatic interactions with Thr117. The lower affinities of TDCs to fish TTR, in particular the polar ones, could potentially lead to milder thyroid-related effects in fish.
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A Structure-based Virtual Screening Protocol for in silico Identification of Potential Thyroid Disrupting Chemicals Targeting Transthyretin.,Zhang J, Begum A, Brannstrom K, Grundstrom C, Iakovleva I, Olofsson A, Sauer-Eriksson AE, Andersson PL Environ Sci Technol. 2016 Sep 26. PMID:27668830<ref>PMID:27668830</ref>
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Interspecies Variation Between Fish and Human Transthyretins in Their Binding of Thyroid-Disrupting Chemicals.,Zhang J, Grundstrom C, Brannstrom K, Iakovleva I, Lindberg M, Olofsson A, Andersson PL, Sauer-Eriksson AE Environ Sci Technol. 2018 Sep 18. doi: 10.1021/acs.est.8b03581. PMID:30226982<ref>PMID:30226982</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
<div class="pdbe-citations 6grp" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 6grp" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Transthyretin|Transthyretin]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Large Structures]]
[[Category: Andersson, P L]]
[[Category: Andersson, P L]]
[[Category: Grundstrom, C]]
[[Category: Grundstrom, C]]

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Crystal Structure Of Human Transthyretin in complex with 3,5,6-trichloro-2-pyridinol (TC2P)

PDB ID 6grp

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