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== | ==Kinetic stabilization of transthyretin through covalent modification of K15 by (E)-N-(4-(4-hydroxy-3,5-dimethylstyryl)ethanesulfonamide== | ||
[[http://www.uniprot.org/uniprot/TTHY_HUMAN TTHY_HUMAN | <StructureSection load='4hjs' size='340' side='right'caption='[[4hjs]], [[Resolution|resolution]] 1.22Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4hjs]] 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=4HJS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HJS 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]] 1.22Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=18J:N-{4-[(E)-2-(4-HYDROXY-3,5-DIMETHYLPHENYL)ETHENYL]PHENYL}ETHANESULFONAMIDE'>18J</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=4hjs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hjs OCA], [https://pdbe.org/4hjs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hjs RCSB], [https://www.ebi.ac.uk/pdbsum/4hjs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hjs 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 == | |||
Small molecules that react selectively with a specific non-enzyme drug-target protein in a complex biological environment without displacement of a leaving group (tracelessly) are rare and highly desirable. Herein we describe the development of a family of fluorogenic stilbene-based vinyl amides and vinyl sulfonamides that covalently modify transthyretin (TTR) tracelessly. These small molecules bind selectively to TTR in complex biological environments and then undergo a rapid and chemoselective 1,4-Michael addition with the pKa-perturbed Lys-15 epsilon-amino group of TTR. Replacing the vinyl amide in 2 with the more reactive vinyl sulfonamide in 4 hastens the conjugation kinetics. X-ray cocrystallography verified the formation of the secondary amine bond mediating the conjugation in the case of 2 and 4 and confirmed the expected orientation of the stilbene within the TTR binding sites. Vinyl amide 2 and vinyl sulfonamide 4 potently inhibit TTR dissociation and amyloid fibril formation in vitro. The TTR binding selectivity, modification yield, and reaction chemoselectivity of vinyl sulfonamide 4 are good enough in human plasma to serve as a starting point for medicinal chemistry efforts. Moreover, vinyl sulfonamide 4 is fluorogenic: it exhibits minimal background fluorescence in complex biological environments, remains dark upon binding to TTR, and becomes fluorescent only upon reaction with TTR. The fluorogenicity of 4 was utilized to accurately quantify the native TTR concentration in Escherichia coli lysate using a fluorescence plate reader. | |||
Stilbene vinyl sulfonamides as fluorogenic sensors of and traceless covalent kinetic stabilizers of transthyretin that prevent amyloidogenesis.,Suh EH, Liu Y, Connelly S, Genereux JC, Wilson IA, Kelly JW J Am Chem Soc. 2013 Nov 27;135(47):17869-80. doi: 10.1021/ja408230k. Epub 2013, Nov 18. PMID:24180271<ref>PMID:24180271</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4hjs" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Transthyretin 3D structures|Transthyretin 3D structures]] | |||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Connelly S]] | |||
[[Category: Wilson IA]] | |||