OCA at 08:43, 6 November 2019

OCA — Wed, 06 Nov 2019 08:43:20 GMT

←Older revision		Revision as of 08:43, 6 November 2019
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-	'''Unreleased structure'''

-	The entry ~~6r6i~~ is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of transthyretin mutant A25T in complex with CHF5074, a flurbiprofen analogue==
		+	<StructureSection load='6r6i' size='340' side='right'caption='[[6r6i]], [[Resolution\|resolution]] 1.47Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6r6i]] 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=6R6I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6R6I FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=H50:1-(3,4-DICHLORO-2-FLUOROBIPHENYL-4-YL)CYCLOPROPANECARBOXYLIC+ACID'>H50</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=6r6i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6r6i OCA], [http://pdbe.org/6r6i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6r6i RCSB], [http://www.ebi.ac.uk/pdbsum/6r6i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6r6i 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 ==
		+	The inherent amyloidogenic potentialof wild type transthyretin (TTR) is enhanced by a large number of point mutations, which destabilize the TTR tetramer, thereby promoting its disassembly and pathological aggregation responsible for TTR-related amyloidosis. TTR stabilizers are able to interact with the thyroxine-binding sites of TTR, stabilizing its tetrameric native state and inhibiting amyloidogenesis. Herein, we report on in vitro, ex vivo, and X-ray analyses to assess the TTR structural stabilization by analogues of flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID). Overall, considering together binding selectivity and protective effects on TTR native structure by flurbiprofen analogues in the presence of plasma proteins, as determined by Western Blot,the aforementioned properties of analyzed compounds appear to be better (CHF5075 and CHF4802) or similar (CHF4795) or worse (CHF5074, also known as CSP-1103) as compared to those of diflunisal, used as a reference TTR stabilizer. Molecular details of the determinants affecting the interactionsof CHF5075, CHF4802, and CHF4795 with wild type TTRand of CHF5074 withtheamyloidogenic A25TTTR variant havebeen elucidated by X-ray analysis. Distinct interactions with TTR appear to characterize flurbiprofen analogues and the NSAID diflunisal and its analogues as TTR stabilizers. Relationships between stabilizing effect on TTR by flurbiprofen analogues determined experimentally and molecular details of their interactions with TTR have been established, providing the rationale for their protective effects on the native protein structure.

-	~~Authors: Loconte~~, V., Menozzi, I., Ferrari, A., ~~Berni~~, R., Zanotti, G.	+	Structure-activity relationships of flurbiprofen analogues as stabilizers of the amyloidogenic protein transthyretin.,Loconte V, Menozzi I, Ferrari A, Folli C, Imbimbo BP, Zanotti G, Berni R J Struct Biol. 2019 Nov 1;208(2):165-173. doi: 10.1016/j.jsb.2019.08.011. Epub, 2019 Aug 29. PMID:31473362<ref>PMID:31473362</ref>

-	~~Description: Crystal structure of transthyretin mutant A25T in complex with CHF5074~~, a ~~flurbiprofen analogue~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6r6i" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Berni, R]]		[[Category: Berni, R]]
		+	[[Category: Ferrari, A]]
	[[Category: Loconte, V]]		[[Category: Loconte, V]]
-	[[Category: Zanotti, G]]
	[[Category: Menozzi, I]]		[[Category: Menozzi, I]]
-	[[Category: ~~Ferrari~~, A]]	+	[[Category: Zanotti, G]]
		+	[[Category: Amyloidosis]]
		+	[[Category: Binding protein]]
		+	[[Category: Tetramer]]
		+	[[Category: Transport protein]]

OCA: Protected "6r6i" [edit=sysop:move=sysop]

OCA — Wed, 03 Apr 2019 05:03:11 GMT

Protected "6r6i" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:03, 3 April 2019

OCA: New page: '''Unreleased structure''' The entry 6r6i is ON HOLD until Paper Publication Authors: Loconte, V., Menozzi, I., Ferrari, A., Berni, R., Zanotti, G. Description: Crystal structure of tr...

OCA — Wed, 03 Apr 2019 05:03:09 GMT

New page: '''Unreleased structure''' The entry 6r6i is ON HOLD until Paper Publication Authors: Loconte, V., Menozzi, I., Ferrari, A., Berni, R., Zanotti, G. Description: Crystal structure of tr...

New page

'''Unreleased structure'''

The entry 6r6i is ON HOLD until Paper Publication

Authors: Loconte, V., Menozzi, I., Ferrari, A., Berni, R., Zanotti, G.

Description: Crystal structure of transthyretin mutant A25T in complex with CHF5074, a flurbiprofen analogue
[[Category: Unreleased Structures]]
[[Category: Berni, R]]
[[Category: Loconte, V]]
[[Category: Zanotti, G]]
[[Category: Menozzi, I]]
[[Category: Ferrari, A]]

6r6i - Revision history

OCA at 08:43, 6 November 2019

OCA: Protected "6r6i" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 6r6i is ON HOLD until Paper Publication Authors: Loconte, V., Menozzi, I., Ferrari, A., Berni, R., Zanotti, G. Description: Crystal structure of tr...