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000912259 1001_ $$00000-0001-9948-7493$$aAntonschmidt, Leif$$b0
000912259 245__ $$aThe clinical drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils
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000912259 520__ $$aAggregation of amyloidogenic proteins is a characteristic of multiple neurodegenerative diseases. Atomic resolution of small molecule binding to such pathological protein aggregates is of interest for the development of therapeutics and diagnostics. Here we investigate the interaction between α-synuclein fibrils and anle138b, a clinical drug candidate for disease modifying therapy in neurodegeneration and a promising scaffold for positron emission tomography tracer design. We used nuclear magnetic resonance spectroscopy and the cryogenic electron microscopy structure of α-synuclein fibrils grown in the presence of lipids to locate anle138b within a cavity formed between two β-strands. We explored and quantified multiple binding modes of the compound in detail using molecular dynamics simulations. Our results reveal stable polar interactions between anle138b and backbone moieties inside the tubular cavity of the fibrils. Such cavities are common in other fibril structures as well.
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000912259 7001_ $$0P:(DE-HGF)0$$aMatthes, Dirk$$b1
000912259 7001_ $$00000-0003-0579-9088$$aDervişoğlu, Rıza$$b2
000912259 7001_ $$0P:(DE-Juel1)172887$$aFrieg, Benedikt$$b3
000912259 7001_ $$00000-0002-2172-5110$$aDienemann, Christian$$b4
000912259 7001_ $$0P:(DE-HGF)0$$aLeonov, Andrei$$b5
000912259 7001_ $$0P:(DE-HGF)0$$aNimerovsky, Evgeny$$b6
000912259 7001_ $$0P:(DE-HGF)0$$aSant, Vrinda$$b7
000912259 7001_ $$0P:(DE-HGF)0$$aRyazanov, Sergey$$b8
000912259 7001_ $$0P:(DE-HGF)0$$aGiese, Armin$$b9
000912259 7001_ $$0P:(DE-Juel1)132018$$aSchröder, Gunnar F.$$b10
000912259 7001_ $$00000-0003-2041-5740$$aBecker, Stefan$$b11
000912259 7001_ $$00000-0003-3570-3534$$ade Groot, Bert L.$$b12$$eCorresponding author
000912259 7001_ $$00000-0002-1266-4344$$aGriesinger, Christian$$b13$$eCorresponding author
000912259 7001_ $$00000-0003-3216-9065$$aAndreas, Loren B.$$b14$$eCorresponding author
000912259 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-022-32797-w$$gVol. 13, no. 1, p. 5385$$n1$$p5385$$tNature Communications$$v13$$x2041-1723$$y2022
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