TY  - JOUR
AU  - Antonschmidt, Leif
AU  - Matthes, Dirk
AU  - Dervişoğlu, Rıza
AU  - Frieg, Benedikt
AU  - Dienemann, Christian
AU  - Leonov, Andrei
AU  - Nimerovsky, Evgeny
AU  - Sant, Vrinda
AU  - Ryazanov, Sergey
AU  - Giese, Armin
AU  - Schröder, Gunnar F.
AU  - Becker, Stefan
AU  - de Groot, Bert L.
AU  - Griesinger, Christian
AU  - Andreas, Loren B.
TI  - The clinical drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils
JO  - Nature Communications
VL  - 13
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - FZJ-2022-05456
SP  - 5385
PY  - 2022
AB  - Aggregation 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.
LB  - PUB:(DE-HGF)16
C6  - 36104315
UR  - <Go to ISI:>//WOS:000853935100020
DO  - DOI:10.1038/s41467-022-32797-w
UR  - https://juser.fz-juelich.de/record/912259
ER  -