OCA at 08:32, 9 May 2024

OCA — Thu, 09 May 2024 08:32:02 GMT

←Older revision		Revision as of 08:32, 9 May 2024
Line 1:		Line 1:
-	'''Unreleased structure'''

-	The entry ~~8pm8~~ is ~~ON HOLD until Paper~~ Publication	+	==V30M Transthyretin structure in complex with Tolcalpone==
		+	<StructureSection load='8pm8' size='340' side='right'caption='[[8pm8]], [[Resolution\|resolution]] 1.57Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8pm8]] 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=8PM8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8PM8 FirstGlance]. <br>
		+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.57Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TCW:TOLCAPONE'>TCW</scene></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8pm8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8pm8 OCA], [https://pdbe.org/8pm8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8pm8 RCSB], [https://www.ebi.ac.uk/pdbsum/8pm8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8pm8 ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[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>
		+	== Function ==
		+	[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>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The aggregation of wild-type transthyretin (TTR) and over 130 genetic TTR variants underlies a group of lethal disorders named TTR amyloidosis (ATTR). TTR chemical chaperones are molecules that hold great promise to modify the course of ATTR progression. In previous studies, we combined rational design and molecular dynamics simulations to generate a series of TTR selective kinetic stabilizers displaying exceptionally high affinities. In an effort to endorse the previously developed molecules with optimal pharmacokinetic properties, we conducted structural design optimization, leading to the development of PITB. PITB binds with high affinity to TTR, effectively inhibiting tetramer dissociation and aggregation of both the wild-type protein and the two most prevalent disease-associated TTR variants. Importantly, PITB selectively binds and stabilizes TTR in plasma, outperforming tolcapone, a drug currently undergoing clinical trials for ATTR. Pharmacokinetic studies conducted on mice confirmed that PITB exhibits encouraging pharmacokinetic properties, as originally intended. Furthermore, PITB demonstrates excellent oral bioavailability and lack of toxicity. These combined attributes position PITB as a lead compound for future clinical trials as a disease-modifying therapy for ATTR.

-	~~Authors~~: ~~Varejao, N~~., Pinheiro, F., ~~Pallares~~, I., Ventura, S., ~~Reverter, D~~.	+	PITB: A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties.,Pinheiro F, Varejao N, Sanchez-Morales A, Bezerra F, Navarro S, Velazquez-Campoy A, Busque F, Almeida MR, Alibes R, Reverter D, Pallares I, Ventura S Eur J Med Chem. 2023 Dec 5;261:115837. doi: 10.1016/j.ejmech.2023.115837. Epub , 2023 Oct 6. PMID:37837673<ref>PMID:37837673</ref>

-	~~Description~~: ~~V30M Transthyretin structure in complex with Tolcalpone~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: ~~Ventura, S~~]]	+	<div class="pdbe-citations 8pm8" style="background-color:#fffaf0;"></div>
-	[[Category: Pinheiro, F]]	+	== References ==
-	[[Category: ~~Varejao, N~~]]	+	<references/>
-	[[Category: ~~Reverter, D~~]]	+	__TOC__
-	[[Category: ~~Pallares, I~~]]	+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Pallares I]]
		+	[[Category: Pinheiro F]]
		+	[[Category: Reverter D]]
		+	[[Category: Varejao N]]
		+	[[Category: Ventura S]]

OCA at 10:55, 26 July 2023

OCA — Wed, 26 Jul 2023 10:55:04 GMT

←Older revision		Revision as of 10:55, 26 July 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8pm8 is ON HOLD	+	The entry 8pm8 is ON HOLD until Paper Publication

	Authors: Varejao, N., Pinheiro, F., Pallares, I., Ventura, S., Reverter, D.		Authors: Varejao, N., Pinheiro, F., Pallares, I., Ventura, S., Reverter, D.

OCA: Protected "8pm8" [edit=sysop:move=sysop]

OCA — Wed, 05 Jul 2023 04:19:53 GMT

Protected "8pm8" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:19, 5 July 2023

OCA: New page: '''Unreleased structure''' The entry 8pm8 is ON HOLD Authors: Varejao, N., Pinheiro, F., Pallares, I., Ventura, S., Reverter, D. Description: V30M Transthyretin structure in complex wi...

OCA — Wed, 05 Jul 2023 04:19:52 GMT

New page: '''Unreleased structure''' The entry 8pm8 is ON HOLD Authors: Varejao, N., Pinheiro, F., Pallares, I., Ventura, S., Reverter, D. Description: V30M Transthyretin structure in complex wi...

New page

'''Unreleased structure'''

The entry 8pm8 is ON HOLD

Authors: Varejao, N., Pinheiro, F., Pallares, I., Ventura, S., Reverter, D.

Description: V30M Transthyretin structure in complex with Tolcalpone
[[Category: Unreleased Structures]]
[[Category: Ventura, S]]
[[Category: Pinheiro, F]]
[[Category: Varejao, N]]
[[Category: Reverter, D]]
[[Category: Pallares, I]]

8pm8 - Revision history

OCA at 08:32, 9 May 2024

OCA at 10:55, 26 July 2023

OCA: Protected "8pm8" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 8pm8 is ON HOLD Authors: Varejao, N., Pinheiro, F., Pallares, I., Ventura, S., Reverter, D. Description: V30M Transthyretin structure in complex wi...