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In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases, deposits of aggregated disease-specific proteins are found. Oligomeric aggregates are presumed to be the key neurotoxic agent. Here we describe the novel oligomer modulator anle138b [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole], an(More)
While we could show that anle138b is capable of prolonging the survival of prion-infected mice even after onset of symptoms, it had remained unclear whether anle138b is also effective in animal models of pD when treatment is started secondary to clinical disease onset. The effect of a compound after onset of symptoms is an important prerequisite for its use(More)
In this article, approaches towards the paramagnetic tagging of diamagnetic proteins are reviewed. Alignment can be achieved by adding paramagnetic fusion proteins or peptides to the C- or the N-terminus or by attaching paramagnetic tags to Cystein residues. Applications for the study of homodimer structures and protein/ligand interactions, as well as(More)
We describe the synthetic route to ethylenediaminetetraacetic acid (EDTA) derivatives that can be attached to surface-exposed thiol functional groups of cysteine residues in proteins, via a methylthiosulfonate moiety that is connected in a stereochemically unique way to the C-1 carbon atom of EDTA. Such compounds can be used to align proteins in solution(More)
[structure: see text] A short synthesis of EDTA-based metal chelates that can be attached to the cysteine residue of a protein via a disulfide bond is described. The complexes were used after coordination of lanthanides to align trigger factor and apo-calmodulin in solution to yield residual dipolar couplings and pseudocontact shifts. Alignment tensors for(More)
Phosphatidylinositol-4,5-bisphosphate (PIP2) is a key player in the neurotransmitter release process. Rabphilin-3A is a neuronal C2 domain tandem containing protein that is involved in this process. Both its C2 domains (C2A and C2B) are able to bind PIP2. The investigation of the interactions of the two C2 domains with the PIP2 headgroup IP3(More)
A DNP set-up is described where a liquid sample is hyperpolarized by the electron-nucleus Overhauser effect in a field of 0.34 T and transferred to a field of 14.09 T for NMR detection. In contrast to a previous set-up, using two dedicated magnets for polarization and detection, a dedicated ferroshim system was inserted into the bore of a 14.09 T shielded(More)
Here we present Cys-Ph-TAHA, a new nonadentate lanthanide tag for the paramagnetic labelling of proteins. The tag can be easily synthesized and is stereochemically homogenous over a wide range of temperatures, yielding NMR spectra with a single set of peaks. Bound to ubiquitin, it induced large residual dipolar couplings and pseudocontact shifts that could(More)
Journal of the American Chemical Society is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Communication Stereochemistry of Sagittamide A from Residual Dipolar Coupling Enhanced NMR Anne Schuetz, Jochen Junker, Andrei Leonov, Oliver F. Lange, Tadeusz F. Molinski, and Christian Griesinger J. Am. Chem. Soc., 2007,(More)
The Ca(2+) binding properties of C2 domains are essential for the function of their host proteins. We present here the first crystal structures showing an unexpected Ca(2+) binding mode of the C2B domain of rabphilin-3A in atomic detail. Acidic residues from the linker region between the C2A and C2B domains of rabphilin-3A interact with the Ca(2+)-binding(More)