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==Crystal Structure Of Sea Bream Transthyretin in complex with 3,5,6-trichloro-2-pyridinol (TC2P)== | ==Crystal Structure Of Sea Bream Transthyretin in complex with 3,5,6-trichloro-2-pyridinol (TC2P)== | ||
<StructureSection load='6gnp' size='340' side='right' caption='[[6gnp]], [[Resolution|resolution]] 2.02Å' scene=''> | <StructureSection load='6gnp' size='340' side='right'caption='[[6gnp]], [[Resolution|resolution]] 2.02Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6gnp]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GNP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GNP FirstGlance]. <br> | <table><tr><td colspan='2'>[[6gnp]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Aurata_aurata Aurata aurata]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GNP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GNP 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></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></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=6gnp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gnp OCA], [http://pdbe.org/6gnp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gnp RCSB], [http://www.ebi.ac.uk/pdbsum/6gnp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gnp 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=6gnp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gnp OCA], [http://pdbe.org/6gnp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gnp RCSB], [http://www.ebi.ac.uk/pdbsum/6gnp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gnp ProSAT]</span></td></tr> | ||
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<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Thyroid | 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 (>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. | ||
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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 6gnp" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6gnp" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Transthyretin|Transthyretin]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Aurata aurata]] | |||
[[Category: Large Structures]] | |||
[[Category: Andersson, P L]] | [[Category: Andersson, P L]] | ||
[[Category: Grundstrom, C]] | [[Category: Grundstrom, C]] | ||
Latest revision as of 10:55, 24 April 2019
Crystal Structure Of Sea Bream Transthyretin in complex with 3,5,6-trichloro-2-pyridinol (TC2P)Crystal Structure Of Sea Bream Transthyretin in complex with 3,5,6-trichloro-2-pyridinol (TC2P)
Structural highlights
Publication Abstract from PubMedThyroid-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 (>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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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