FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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References
Sustainable synthesis and automated deposition: an accessible discovery screening library of fragment-like purines
Kamper(*), C., Korpis(*), K., Specker, E., Anger, L., Neuenschwander, M., Bednarski(*), P. J.; Link(*), A.
Mol Divers, 16:541-551
(2012)

Tags: Screening Unit (von Kries)

Abstract: A sub-library of 88 information-rich lead-like purine derivatives were prepared and deposited in an open access academic screening facility. The rationale for the synthesis of these rigid low complexity structures was the privileged character of the purine heterocycle associated with its inherent probability of interactions with multiple adenine-related targets. Although generally expected to be weak binders in many assays, such fragment-like compounds are estimated to match diverse binding sites. It is suggested that heterocycles with many anchor points for hydrogen bonds can be anticipated to undergo very specific interactions to produce more negative enthalpies and thus provide superior starting points for lead optimization than compounds that owe their activity to entropic effects. The in vitro cytotoxicity of the small compounds on a panel of human cancer cell lines has been investigated and some of them showed marked unselective or selective toxicity. This data may be useful if these fragments are to be incorporated into drug-like structures via metabolically cleavable connections. The sub-library will be implemented as part of the ChemBioNet (www.chembionet.info) library, and it is open to screening campaigns of academic research groups striving for a fragment-based approach in their biological assays.

Rapid solid-state NMR of deuterated proteins by interleaved cross-polarization from H-1 and H-2 nuclei
Bjerring(*), M., Paaske(*), B., Oschkinat, H., Akbey, Ü.; Nielsen(*), N. C.
Journal of Magnetic Resonance, 214:324-328
(2012)

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: We present a novel sampling strategy, interleaving acquisition of multiple NMR spectra by exploiting initial polarization subsequently from H-1 and H-2 spins, taking advantage of their different T-1 relaxation times. Different H-1- and H-2-polarization based spectra are in this way simultaneously recorded improving either information content or sensitivity by adding spectra. The so-called Relaxation-optimized Acquisition of Proton Interleaved with Deuterium (RAPID) H-1 -> C-13/H-2 -> C-13 CP/MAS multiple-acquisition method is demonstrated by 1D and 2D experiments using a uniformly H-2, N-15, C-13-labeled alpha-spectrin SH3 domain sample with all or 30% back-exchanged labile H-2 to H-1. It is demonstrated how 1D C-13 CP/MAS or 2D C-13-C-13 correlation spectra initialized with polarization from either H-1 or H-2 may be recorded simultaneously with flexibility to be added or used individually for spectral editing. It is also shown how 2D C-13-C-13 correlation spectra may be recorded interleaved with H-2-C-13 correlation spectra to obtain C-13-C-13 correlations along with information about dynamics from H-2 sideband patterns. (C) 2011 Elsevier Inc. All rights reserved.

A comparison of NCO and NCA transfer methods for biological solid-state NMR spectroscopy
Loening, N. M., Bjerring(*), M., Nielsen(*), N. C.; Oschkinat, H.
Journal of Magnetic Resonance, 214:81-90
(2012)

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: Three different techniques (adiabatic passage Hartman-Hahn cross-polarization, optimal control designed pulses, and EXPORT) are compared for transferring N-15 magnetization to C-13 in solid-state NMR experiments under magic-angle-spinning conditions. We demonstrate that, in comparison to adiabatic passage Hartman-Hahn cross-polarization, optimal control transfer pulses achieve similar or better transfer efficiencies for uniformly-C-13,N-15 labeled samples and are generally superior for samples with non-uniform labeling schemes (such as 1,3- and 2-C-13 glycerol labeling). In addition, the optimal control pulses typically use substantially lower average RF field strengths and are more robust with respect to experimental variation and RF inhomogeneity. Consequently, they are better suited for demanding samples. (C) 2011 Elsevier Inc. All rights reserved.

GlialCAM, a Protein Defective in a Leukodystrophy, Serves as a CIC-2 Cl- Channel Auxiliary Subunit
Jeworutzki(*), E., Lopez-Hernandez(*), T., Capdevila-Nortes(*), X., Sirisi(*), S., Bengtsson, L., Montolio(*), M., Zifarelli(*), G., Arnedo(*), T., Müller(*), C. S., Schulte(*), U., Nunes(*), V., Martinez(*), A., Jentsch, T. J., Gasull(*), X., Pusch(*), M.; Estevez(*), R.
Neuron, 73:951-961
(2012)

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: Ion fluxes mediated by glial cells are required for several physiological processes such as fluid homeostasis or the maintenance of low extracellular potassium during high neuronal activity. In mice, the disruption of the Cl- channel CIC-2 causes fluid accumulation leading to myelin vacuolation. A similar vacuolation phenotype is detected in humans affected with megalencephalic leukoencephalopathy with subcortical cysts (MLC), a leukodystrophy which is caused by mutations in MLC1 or GLIALCAM. We here identify GlialCAM as a CIC-2 binding partner. GlialCAM and CIC-2 colocalize in Bergmann glia, in astrocyte-astrocyte junctions at astrocytic endfeet around blood vessels, and in myelinated fiber tracts. GlialCAM targets CIC-2 to cell junctions, increases CIC-2 mediated currents, and changes its functional properties. Disease-causing GLIALCAM mutations abolish the targeting of the channel to cell junctions. This work describes the first auxiliary subunit of CIC-2 and suggests that CIC-2 may play a role in the pathology of MLC disease.

ARIA for solution and solid-state NMR
Bardiaux, B., Malliavin(*), T.; Nilges(*), M.
Methods Mol Biol, 831:453-483
(2012)

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: In solution or solid-state, determining the three-dimensional structure of biomolecules by Nuclear -Magnetic Resonance (NMR) normally requires the collection of distance information. The interpretation of the spectra containing this distance information is a critical step in an NMR structure determination. In this chapter, we present the Ambiguous Restraints for Iterative Assignment (ARIA) program for automated cross-peak assignment and determination of macromolecular structure from solution and solid-state NMR experiments. While the program was initially designed for the assignment of nuclear Overhauser effect (NOE) resonances, it has been extended to the interpretation of magic-angle spinning (MAS) solid-state NMR data. This chapter first details the concepts and procedures carried out by the program. Then, we describe both the general strategy for structure determination with ARIA 2.3 and practical aspects of the technique. ARIA 2.3 includes all recent developments. such as an extended integration of the Collaborative Computing Project for the NMR community (CCPN), the incorporation of the log-harmonic distance restraint potential and an automated treatment of symmetric oligomers.

Efficient Modeling of Symmetric Protein Aggregates from NMR Data
Bardiaux, B., van Rossum, B. J., Nilges(*), M.; Oschkinat, H.
Angew Chem Int Edit, 51:6916-6919
(2012)

Tags: NMR-Supported Structural Biology (Oschkinat)

Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer's disease
Schmidt(*), V., Baum(*), K., Lao(*), A., Rateitschak(*), K., Schmitz(*), Y., Teichmann, A., Wiesner, B., Petersen(*), C. M., Nykjaer(*), A., Wolf(*), J., Wolkenhauer(*), O.; Willnow(*), T. E.
Embo j, 31:187-200
(2012)

Tags: Cellular Imaging (Wiesner)

Abstract: The extent of proteolytic processing of the amyloid precursor protein (APP) into neurotoxic amyloid-beta (Abeta) peptides is central to the pathology of Alzheimer's disease (AD). Accordingly, modifiers that increase Abeta production rates are risk factors in the sporadic form of AD. In a novel systems biology approach, we combined quantitative biochemical studies with mathematical modelling to establish a kinetic model of amyloidogenic processing, and to evaluate the influence by SORLA/SORL1, an inhibitor of APP processing and important genetic risk factor. Contrary to previous hypotheses, our studies demonstrate that secretases represent allosteric enzymes that require cooperativity by APP oligomerization for efficient processing. Cooperativity enables swift adaptive changes in secretase activity with even small alterations in APP concentration. We also show that SORLA prevents APP oligomerization both in cultured cells and in the brain in vivo, eliminating the preferred form of the substrate and causing secretases to switch to a less efficient non-allosteric mode of action. These data represent the first mathematical description of the contribution of genetic risk factors to AD substantiating the relevance of subtle changes in SORLA levels for amyloidogenic processing as proposed for patients carrying SORL1 risk alleles.

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