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Hora, M. ; Carballo-Pacheco, M.* ; Weber, B.* ; Morris, V.K.* ; Wittkopf, A.* ; Buchner, J.* ; Strodel, B.* ; Reif, B.

Epigallocatechin-3-gallate preferentially induces aggregation of amyloidogenic immunoglobulin light chains.

Sci. Rep. 7:41515 (2017)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Antibody light chain amyloidosis is a rare disease caused by fibril formation of secreted immunoglobulin light chains (LCs). The huge variety of antibody sequences puts a serious challenge to drug discovery. The green tea polyphenol epigallocatechin-3-gallate (EGCG) is known to interfere with fibril formation in general. Here we present solution-and solid-state NMR studies as well as MD simulations to characterise the interaction of EGCG with LC variable domains. We identified two distinct EGCG binding sites, both of which include a proline as an important recognition element. The binding sites were confirmed by site-directed mutagenesis and solid-state NMR analysis. The EGCG-induced protein complexes are unstructured. We propose a general mechanistic model for EGCG binding to a conserved site in LCs. We find that EGCG reacts selectively with amyloidogenic mutants. This makes this compound a promising lead structure, that can handle the immense sequence variability of antibody LCs.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Primary Systemic Amyloidosis; V-l Domain; Green Tea; Al Amyloidosis; Thermal-stability; Crystal-structure; Variable Domains; Nmr-spectroscopy; Fibril Formation; Constant-region
Sprache englisch
Veröffentlichungsjahr 2017
HGF-Berichtsjahr 2017
ISSN (print) / ISBN 2045-2322
e-ISSN 2045-2322
Zeitschrift Scientific Reports
Quellenangaben Band: 7, Heft: , Seiten: , Artikelnummer: 41515 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503090-001
PubMed ID 28128355
DOI 10.1038/srep41515
WOS ID WOS:000392794800001
Scopus ID 85010966182
Erfassungsdatum 2017-03-21
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