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000140404 0247_ $$2doi$$a10.1021/acschemneuro.8b00182
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000140404 037__ $$aDZNE-2020-06726
000140404 041__ $$aEnglish
000140404 082__ $$a540
000140404 1001_ $$0P:(DE-HGF)0$$aKiss, Róbert$$b0
000140404 245__ $$aStructural Basis of Small Molecule Targetability of Monomeric Tau Protein.
000140404 260__ $$aWashington, DC$$bACS Publ.$$c2018
000140404 264_1 $$2Crossref$$3online$$bAmerican Chemical Society (ACS)$$c2018-06-26
000140404 264_1 $$2Crossref$$3print$$bAmerican Chemical Society (ACS)$$c2018-12-19
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000140404 520__ $$aThe therapeutic targeting of intrinsically disordered proteins (IDPs) by small molecules has been a challenge due to their heterogeneous conformational ensembles. A potential therapeutic strategy to alleviate the aggregation of IDPs is to maintain them in their native monomeric state by small molecule binding. This study investigates the structural basis of small molecule druggability of native monomeric Tau whose aggregation is linked to the onset of Tauopathies such as Alzheimer's disease. Initially, two available monomeric conformational ensembles of a shorter Tau construct K18 (also termed Tau4RD) were analyzed which revealed striking structural differences between the two ensembles, while similar number of hot spots and small molecule binding sites were identified on monomeric Tau ensembles as on tertiary folded proteins of similar size. Remarkably, some critical fibril forming sequence regions of Tau (V306-K311, V275-K280) participated in hot spot formation with higher frequency compared to other regions. As an example of small molecule binding to monomeric Tau, it was shown that methylene blue (MB) bound to monomeric K18 and full-length Tau selectively with high affinity (Kd = 125.8 nM and 86.6 nM, respectively) with binding modes involving Cys291 and Cys322, previously reported to be oxidized in the presence of MB. Overall, our results provide structure-based evidence that Tau can be a viable drug target for small molecules and indicate that specific small molecules may be able to bind to monomeric Tau and influence the way in which the protein interacts among itself and with other proteins.
000140404 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
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000140404 650_7 $$2NLM Chemicals$$aIntrinsically Disordered Proteins
000140404 650_7 $$2NLM Chemicals$$aMAPT protein, human
000140404 650_7 $$2NLM Chemicals$$atau Proteins
000140404 650_7 $$0T42P99266K$$2NLM Chemicals$$aMethylene Blue
000140404 650_2 $$2MeSH$$aHumans
000140404 650_2 $$2MeSH$$aIntrinsically Disordered Proteins: metabolism
000140404 650_2 $$2MeSH$$aMethylene Blue: metabolism
000140404 650_2 $$2MeSH$$aMolecular Docking Simulation
000140404 650_2 $$2MeSH$$aMolecular Targeted Therapy
000140404 650_2 $$2MeSH$$aNeurofibrillary Tangles: metabolism
000140404 650_2 $$2MeSH$$aProtein Structure, Tertiary
000140404 650_2 $$2MeSH$$aTauopathies: metabolism
000140404 650_2 $$2MeSH$$atau Proteins: chemistry
000140404 650_2 $$2MeSH$$atau Proteins: metabolism
000140404 650_2 $$2MeSH$$atau Proteins: ultrastructure
000140404 7001_ $$0P:(DE-HGF)0$$aCsizmadia, Georgina$$b1
000140404 7001_ $$0P:(DE-HGF)0$$aSolti, Katalin$$b2
000140404 7001_ $$0P:(DE-HGF)0$$aKeresztes, Attila$$b3
000140404 7001_ $$0P:(DE-HGF)0$$aZhu, Max$$b4
000140404 7001_ $$0P:(DE-2719)2810282$$aPickhardt, Marcus$$b5$$udzne
000140404 7001_ $$0P:(DE-2719)2541671$$aMandelkow, Eckhard$$b6$$udzne
000140404 7001_ $$0P:(DE-HGF)0$$aTóth, Gergely$$b7$$eCorresponding author
000140404 77318 $$2Crossref$$3journal-article$$a10.1021/acschemneuro.8b00182$$b : American Chemical Society (ACS), 2018-06-26$$n12$$p2997-3006$$tACS Chemical Neuroscience$$v9$$x1948-7193$$y2018
000140404 773__ $$0PERI:(DE-600)2528493-9$$a10.1021/acschemneuro.8b00182$$gVol. 9, no. 12, p. 2997 - 3006$$n12$$p2997 - 3006$$q9:12<2997 - 3006$$tACS chemical neuroscience$$v9$$x1948-7193$$y2018
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000140404 9141_ $$y2018
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