6grp - Revision history

OCA at 07:56, 24 April 2019

2019-04-24T07:56:03Z

←Older revision		Revision as of 07:56, 24 April 2019
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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)==
-	<StructureSection load='6grp' size='340' side='right' caption='[[6grp]], [[Resolution\|resolution]] 1.60Å' scene=''>	+	<StructureSection load='6grp' size='340' side='right'caption='[[6grp]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<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>		<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>
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	</div>		</div>
	<div class="pdbe-citations 6grp" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6grp" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Transthyretin\|Transthyretin]]
	== References ==		== References ==
	<references/>		<references/>
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	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Andersson, P L]]		[[Category: Andersson, P L]]
	[[Category: Grundstrom, C]]		[[Category: Grundstrom, C]]

OCA at 08:44, 26 September 2018

2018-09-26T08:44:16Z

←Older revision		Revision as of 08:44, 26 September 2018
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	<StructureSection load='6grp' size='340' side='right' caption='[[6grp]], [[Resolution\|resolution]] 1.60Å' scene=''>		<StructureSection load='6grp' size='340' side='right' caption='[[6grp]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<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>	+	<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>
		+	<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 ==
-	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~~.	+	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.

-	~~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>	+	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>
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Andersson, P L]]		[[Category: Andersson, P L]]
	[[Category: Grundstrom, C]]		[[Category: Grundstrom, C]]

OCA at 05:50, 11 July 2018

2018-07-11T05:50:28Z

←Older revision		Revision as of 05:50, 11 July 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	The entry ~~6grp~~ is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal Structure Of Human Transthyretin in complex with 3,5,6-trichloro-2-pyridinol (TC2P)==
		+	<StructureSection load='6grp' size='340' side='right' caption='[[6grp]], [[Resolution\|resolution]] 1.60Å' scene=''>
		+	== Structural highlights ==
		+	<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>
		+	</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>
		+	<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>
		+	== Disease ==
		+	[[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>
		+	== Function ==
		+	[[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>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	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.

-	~~Authors: Grundstrom, C~~., Zhang, J~~., Olofsson~~, A., ~~Andersson~~, ~~P.L.~~, Sauer-Eriksson, A.E.	+	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>

-	~~Description: Crystal Structure Of Human Transthyretin in complex with 3~~,~~5,6~~-~~trichloro~~-~~2-pyridinol (TC2P)~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	</div>
-	~~[[Category: Sauer-Eriksson, A.E]]~~	+	<div class="pdbe-citations 6grp" style="background-color:#fffaf0;"></div>
-	[[Category: Andersson, P.L]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Andersson, P L]]
	[[Category: Grundstrom, C]]		[[Category: Grundstrom, C]]
	[[Category: Olofsson, A]]		[[Category: Olofsson, A]]
		+	[[Category: Sauer-Eriksson, A E]]
	[[Category: Zhang, J]]		[[Category: Zhang, J]]
		+	[[Category: 6-trichloro-2-pyridinol]]
		+	[[Category: Tc2p]]
		+	[[Category: Tdc]]
		+	[[Category: Thyroxine disrupting chemical]]
		+	[[Category: Transport protein]]
		+	[[Category: Transthyretin]]

OCA at 05:51, 4 July 2018

2018-07-04T05:51:25Z

←Older revision		Revision as of 05:51, 4 July 2018
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6grp is ON HOLD	+	The entry 6grp is ON HOLD until Paper Publication

	Authors: Grundstrom, C., Zhang, J., Olofsson, A., Andersson, P.L., Sauer-Eriksson, A.E.		Authors: Grundstrom, C., Zhang, J., Olofsson, A., Andersson, P.L., Sauer-Eriksson, A.E.

OCA: Protected "6grp" [edit=sysop:move=sysop]

2018-06-20T04:23:50Z

Protected "6grp" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:23, 20 June 2018

OCA: New page: '''Unreleased structure''' The entry 6grp is ON HOLD Authors: Grundstrom, C., Zhang, J., Olofsson, A., Andersson, P.L., Sauer-Eriksson, A.E. Description: Crystal Structure Of Human Tra...

2018-06-20T04:23:49Z

New page: '''Unreleased structure''' The entry 6grp is ON HOLD Authors: Grundstrom, C., Zhang, J., Olofsson, A., Andersson, P.L., Sauer-Eriksson, A.E. Description: Crystal Structure Of Human Tra...

New page

'''Unreleased structure'''

The entry 6grp is ON HOLD

Authors: Grundstrom, C., Zhang, J., Olofsson, A., Andersson, P.L., Sauer-Eriksson, A.E.

Description: Crystal Structure Of Human Transthyretin in complex with 3,5,6-trichloro-2-pyridinol (TC2P)
[[Category: Unreleased Structures]]
[[Category: Sauer-Eriksson, A.E]]
[[Category: Andersson, P.L]]
[[Category: Grundstrom, C]]
[[Category: Olofsson, A]]
[[Category: Zhang, J]]