Papers by Christian Griesinger
Sprachwissenschaftliche Erschließungsmethoden für digitale Editionen mittelhochdeutscher Texte
Das Mittelalter
This paper sheds light on the possibilities and perspectives of linking digital editions of Medie... more This paper sheds light on the possibilities and perspectives of linking digital editions of Medieval German texts to each other and to other digital resources. Furthermore, it discusses some of the internal and technical conditions necessary to render this linkage meaningful, like lemmatisation, part-of-speech-tagging, and using standardised mark-up languages. Finally, the sustainability and reusability of digital editions are considered. While in the past, editions of medieval texts were conceived as rather isolated scholarly works of individual editors, nowadays the collaboration and cooperation of greater working groups is essential in editing projects. Due to the complexity of editions consisting of multiple textual layers, e. g. apparatus entries, annotations, or facsimiles, the requirements for future digital editions have risen. The first approach to respond to these demands is to link the various textual layers to each other, enabling the users to navigate between these laye...
Journal of Cheminformatics
Biophysical journal, Jan 13, 2018
The inherent tendency of proteins to convert from their native states into amyloid aggregates is ... more The inherent tendency of proteins to convert from their native states into amyloid aggregates is associated with a range of human disorders, including Alzheimer's and Parkinson's diseases. In that sense, the use of small molecules as probes for the structural and toxic mechanism related to amyloid aggregation has become an active area of research. Compared with other compounds, the structural and molecular basis behind the inhibitory interaction of phthalocyanine tetrasulfonate (PcTS) with proteins such as αS and tau has been well established, contributing to a better understanding of the amyloid aggregation process in these proteins. We present here the structural characterization of the binding of PcTS and its Cu(II) and Zn(II)-loaded forms to the amyloid β-peptide (Aβ) and the impact of these interactions on the peptide amyloid fibril assembly. Elucidation of the PcTS binding modes to Aβ revealed the involvement of specific aromatic and hydrophobic interactions in the for...
Simultaneous determination of fast and slow dynamics in molecules using extreme CPMG relaxation dispersion experiments
Journal of biomolecular NMR, 2018
Molecular dynamics play a significant role in how molecules perform their function. A critical me... more Molecular dynamics play a significant role in how molecules perform their function. A critical method that provides information on dynamics, at the atomic level, is NMR-based relaxation dispersion (RD) experiments. RD experiments have been utilized for understanding multiple biological processes occurring at micro-to-millisecond time, such as enzyme catalysis, molecular recognition, ligand binding and protein folding. Here, we applied the recently developed high-power RD concept to the Carr-Purcell-Meiboom-Gill sequence (extreme CPMG; E-CPMG) for the simultaneous detection of fast and slow dynamics. Using a fast folding protein, gpW, we have shown that previously inaccessible kinetics can be accessed with the improved precision and efficiency of the measurement by using this experiment.
Measurement of residual chemical shift anisotropies in compressed PMMA gels. Automatic compensation of gel isotropic shift contribution
Magnetic resonance in chemistry : MRC, Jan 11, 2018
Mechanical compression of polymer gels provides a simple way for the measurement of Residual Chem... more Mechanical compression of polymer gels provides a simple way for the measurement of Residual Chemical Shift Anisotropies (RCSAs), which then can be employed, on its own, or in combination with Residual Dipolar Couplings (RDCs), for structural elucidation purposes. RCSAs measured using compression devices needed a posteriori correction to account for the increase of the polymer to solvent ratio inside the swollen gel. This correction has been cast before in terms of a single free parameter which, as shown here, can be simultaneously optimized along with the components of the alignment tensor while still retaining discriminating power of the different relative configurations as illustrated in the stereochemical analysis of α-santonin and 10-epi-8-deoxycumambrin B.
Scientific reports, Jan 4, 2017
Crucial for immune and anti-inflammatory cellular responses, signal transducer and activator of t... more Crucial for immune and anti-inflammatory cellular responses, signal transducer and activator of transcription 6 (STAT6) regulates transcriptional activation in response to interleukin-4 and -13 -induced tyrosine phosphorylation by direct interaction with coactivators. The interaction of STAT6 with nuclear coactivator 1 (NCoA1) is mediated by a short region of the STAT6 transactivation domain that includes the motif LXXLL and interacts with the PAS-B domain of NCoA1. Despite the availability of an X-ray structure of the PAS-B domain/ Leu794-Gly814-STAT6 complex, the mechanistic details of this interaction are still poorly understood. Here, we determine the structure of the NCoA1257-385/STAT6783-814 complex using Nuclear Magnetic Resonance (NMR) and X-ray crystallography. The STAT6783-814 peptide binds with additional N-terminal amino acids to NCoA1257-385, compared to the STAT6794-814 peptide, explaining its higher affinity. Secondary and tertiary structures existing in the free pept...
Journal of the Korean Magnetic Resonance Society
Assignment of carbonyl carbons and sequence analysis in peptides by heteronuclear shift correlation via small coupling constants with broadband decoupling in t1 (COLOC)
Journal of Magnetic Resonance (1969)
Journal of Magnetic Resonance (1969)
Selective excitation of carbonyl resonances in C,H-shift correlation (C,H-COSY) considerably impr... more Selective excitation of carbonyl resonances in C,H-shift correlation (C,H-COSY) considerably improves the resolution. Variations of the basic pulse sequence are discussed with respect to sensitivity and extractability of heteronuclear coupling constants. A procedure based on evaluation of the shift correlation plus a reference ID or 2D proton spectrum combined with simulations is proposed for the quantitative analysis and demonstrated with the example of a cyclic hexapeptide. o 1989 Academic PXSS, IIIC.
Practical aspects of the E.COSY technique. Measurement of scalar spin-spin coupling constants in peptides
Journal of Magnetic Resonance (1969)
Frequency offset effects and their elimination in NMR rotating-frame cross-relaxation spectroscopy
Journal of Magnetic Resonance (1969)
A practical approach to three-dimensional NMR spectroscopy
Journal of Magnetic Resonance (1969)
Journal of Magnetic Resonance (1969)
Nowadays many possibilities exist to elucidate carbon-carbon connectivity. In hydrogen-bearing ca... more Nowadays many possibilities exist to elucidate carbon-carbon connectivity. In hydrogen-bearing carbon systems CC connectivities can be traced out most conveniently in an indirect way by a combination of H-H COSY (I) and H-C CQSY (2). In case of overlapping 'proton signals ambiguities can be removed by heteronuclear relayed spectroscopy (3) and heteronuclear TQCSY (4). By these techniques only protonated carbons are correlated to proton spin systems. Quaternary carbons C, can be assigned by the H-C COLQC experiment (5, 6) connecting protons and carbons coupled over two, three, and in rare cases four bonds (see below). There is no way to differentiate those couplings based upon the number of bonds between the coupling nuclei. To solve such ambiguities, there is the INEPT-INADEQUATE experiment (7) (Fig. la) which directly connects pairs of carbon nuclei. However, this experiment is very insensitive, since it detects only 10e4 of the molecules. We propose here a 1D and a 2D version of a C-relayed heteronuclear experiment. Although it also requires pairs of 13C nuclei it is more sensitive and is tailored uniquely for the moiety C,-CH,. The 1 D version, C-relayed H-C INEPT, is a combination of an H-C INEPT experiment (8) with a subsequent polarization transfer step from carbon to carbon (see Fig. lb). During the delay A, direct H-C coupling evolves and magnetization is transferred to proton-bearing carbons by the pa.ir of 7r/2 pulses. During A,, H-C coupling is refocused and A4 'Jcc coupling evolves. The x pulse in the middle of A4 refocuses chemical-shift evolution. The last 13C x/2 pulse causes the CC polarization transfer. To suppress strong signals from nonquatemary carbons, the delay A3 is inserted before the acquisition. This delay is set to (24-n)-' to produce antiphase magnetization of CH, units (n = l-3). In &, '3C-'3C coupling partially refocuses, which makes a phase correction impossible. Sine-bell multiplication and magnitude calculation remove this problem. We present the phase cycling of this multiphase sequence derived according to Ref. (9) in a condensed form (Table 1). The original phases plus phase increments of each phase program (4, to 4,) are listed together with the reaction of the receiver phase (4,&. S means consecutive phase shifts of 0, 90, 180, and 270", 2s means shifts of 0 and 180". The symbol 1 means that the original phase is 90" instead of zero.
Determination of proton-proton coupling constants in 13C-labeled molecules
Journal of Magnetic Resonance (1969)
Combined use of hard and soft pulses for ω1 decoupling in two-dimensional NMR spectroscopy
Journal of Magnetic Resonance (1969)
Angewandte Chemie (International ed. in English), Jan 15, 2017
G-protein-coupled-receptors (GPCRs) are of fundamental importance for signal transduction through... more G-protein-coupled-receptors (GPCRs) are of fundamental importance for signal transduction through cell membranes. This makes them important drug targets, but structure-based drug design (SBDD) is still hampered by the limitations for structure determination of unmodified GPCRs. We show that the interligand NOEs for pharmacophore mapping (INPHARMA) method can provide valuable information on ligand poses inside the binding site of the unmodified human A2A adenosine receptor reconstituted in nanodiscs. By comparing experimental INPHARMA spectra with back-calculated spectra based on ligand poses obtained from molecular dynamics simulations, a complex structure for A2A R with the low-affinity ligand 3-pyrrolidin-1-ylquinoxalin-2-amine was determined based on the X-ray structure of ligand ZM-241,358 in complex with a modified A2A R.
Solution NMR views of dynamical ordering of biomacromolecules
Biochimica et biophysica acta, Jan 25, 2017
To understand the mechanisms related to the 'dynamical ordering' of macromolecules and bi... more To understand the mechanisms related to the 'dynamical ordering' of macromolecules and biological systems, it is crucial to monitor, in detail, molecular interactions and their dynamics across multiple timescales. Solution nuclear magnetic resonance (NMR) spectroscopy is an ideal tool that can investigate biophysical events at the atomic level, in near-physiological buffer solutions, or even inside cells. Scope of Review In the past several decades, progress in solution NMR has significantly contributed to the elucidation of three-dimensional structures, the understanding of conformational motions, and the underlying thermodynamic and kinetic properties of biomacromolecules. This review discusses recent methodological development of NMR, their applications and some of the remaining challenges. Major Conclusions Although a major drawback of NMR is its difficulty in studying the dynamical ordering of larger biomolecular systems, current technologies have achieved considerable ...
Proceedings of the National Academy of Sciences of the United States of America, Jun 20, 2017
Recent epidemiological and clinical studies have reported a significantly increased risk for mela... more Recent epidemiological and clinical studies have reported a significantly increased risk for melanoma in people with Parkinson's disease. Because no evidence could be obtained that genetic factors are the reason for the association between these two diseases, we hypothesized that of the three major Parkinson's disease-related proteins-α-synuclein, LRRK2, and Parkin-α-synuclein might be a major link. Our data, presented here, demonstrate that α-synuclein promotes the survival of primary and metastatic melanoma cells, which is the exact opposite of the effect that α-synuclein has on dopaminergic neurons, where its accumulation causes neuronal dysfunction and death. Because this detrimental effect of α-synuclein on neurons can be rescued by the small molecule anle138b, we explored its effect on melanoma cells. We found that treatment with anle138b leads to massive melanoma cell death due to a major dysregulation of autophagy, suggesting that α-synuclein is highly beneficial to ...
Nature methods, Feb 1, 2017
We introduce Cryogenic Optical Localization in 3D (COLD), a method to localize multiple fluoresce... more We introduce Cryogenic Optical Localization in 3D (COLD), a method to localize multiple fluorescent sites within a single small protein with Angstrom resolution. We demonstrate COLD by determining the conformational state of the cytosolic Per-ARNT-Sim domain from the histidine kinase CitA of Geobacillus thermodenitrificans and resolving the four biotin sites of streptavidin. COLD provides quantitative 3D information about small- to medium-sized biomolecules on the Angstrom scale and complements other techniques in structural biology.
Proceedings of the National Academy of Sciences of the United States of America, Mar 21, 2017
Bacteria use membrane-integral sensor histidine kinases (HK) to perceive stimuli and transduce si... more Bacteria use membrane-integral sensor histidine kinases (HK) to perceive stimuli and transduce signals from the environment to the cytosol. Information on how the signal is transmitted across the membrane by HKs is still scarce. Combining both liquid- and solid-state NMR, we demonstrate that structural rearrangements in the extracytoplasmic, citrate-sensing Per-Arnt-Sim (PAS) domain of HK CitA are identical for the isolated domain in solution and in a longer construct containing the membrane-embedded HK and lacking only the kinase core. We show that upon citrate binding, the PAS domain contracts, resulting in a shortening of the C-terminal β-strand. We demonstrate that this contraction of the PAS domain, which is well characterized for the isolated domain, is the signal transmitted to the transmembrane (TM) helices in a CitA construct in liposomes. Putting the extracytoplasmic PAS domain into context of the membrane-embedded CitA construct slows down citrate-binding kinetics by at l...
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Papers by Christian Griesinger