期刊
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 27, 期 2, 页码 163-170出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2009.10507306
关键词
Conformational disease; Prion protein; Quinacrine; 9-aminoacridine; Drug design; Ligand binding; NMR-spectroscopy; in vitro binding assay; Relaxation
资金
- Bavarian Prion Research Platform (ForPrion)
- Volkswagen-Stiftung [1/79968]
Tricyclic aromatic compounds (TCA) are promising candidates for treatment of transmissible spongiform encephalopathies. Direct binding to the cellular prion protein (PrPC) has been proposed as anti-prion active mechanism. We here show by means of NMR-spectroscopy that binding of TCA occurs with millimolar affinity to motifs consisting of two neighboring aromatic residues (Ar-Ar motif). It is independent of the secondary structure of this motif and of the side chain attached to the TCA and it is not specific to PrPC. Because biologically inactive 9-aminoacridine (9-aa) binds with similar K-D as anti-prion active quinacrine, direct interaction with PrPC as mechanism of action appears highly unlikely. However, binding of 9-aa to Ar-Ar-motifs in proteins can be used as reporter for biological macromolecule interactions, by measuring changes in T-1-NMR relaxation times of 9-aa.
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