FMP Publications

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

Year:  
All :: 2010, ... , 2012, 2013, 2014, ... , 2017
Author:  
All :: (, A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, X, Y, Z 
  
 
Preferences: 
References per page: Show keywords Show abstracts
References
Cryogenic solid state NMR studies of fibrils of the Alzheimer's disease amyloid-beta peptide: perspectives for DNP
del Amo, J. M. L., Schneider(*), D., Loquet(*), A., Lange(*), A.; Reif, B.
J. Biomol. NMR, 56:359-363
(2013)

Tags: Solid-State NMR Spectroscopy (Reif)

Abstract: Dynamic Nuclear Polarization solid-state NMR holds the potential to enable a dramatic increase in sensitivity by exploiting the large magnetic moment of the electron. However, applications to biological solids are hampered in uniformly isotopically enriched biomacromolecules due to line broadening which yields a limited spectral resolution at cryogenic temperatures. We show here that high magnetic fields allow to overcome the broadening of resonance lines often experienced at liquid nitrogen temperatures. For a fibril sample of the Alzheimer's disease beta-amyloid peptide, we find similar line widths at low temperature and at room temperature. The presented results open new perspectives for structural investigations in the solid-state.

Slice-selective gradient-encoded CEST spectroscopy for monitoring dynamic parameters and high-throughput sample characterization
Döpfert, J., Witte, C.; Schröder, L.
J Magn Reson, 237:34-39
(2013)

Tags: Molecular Imaging (Schröder)

Abstract: Chemical Exchange Saturation Transfer (CEST) NMR is an increasingly used technique for generating molecule or microenvironment specific signal contrast. To characterize CEST agents and to extract parameters such as temperature and pH, it is often required to resolve the spectral dimension. This is achieved by recording so called CEST- or z-spectra, where the spectral CEST information is conventionally acquired point by point, leading to long acquisition times. Here, we employ gradient-encoding to substantially accelerate the acquisition process of z-spectra in phantom experiments, reducing it to only two scans. This speedup allows us to monitor dynamic processes such as rapid temperature changes in a PARACEST sample that would be inaccessible with the conventional encoding. Furthermore, we combine the gradient-encoding approach with multi-slice selection, thus reserving one spatial dimension for the simultaneous investigation of heterogeneous PARACEST sample packages within one experiment. Hence, gradient-encoded CEST might be of great use for high-throughput screening of CEST contrast agents.

What's in a name? Why these proteins are intrinsically disordered: Why these proteins are intrinsically disordered
Dunker(*), A. K., Babu(*), M. M., Barbar(*), E., Blackledge(*), M., Bondos(*), S. E., Dosztanyi(*), Z., Dyson(*), H. J., Forman-Kay(*), J., Fuxreiter(*), M., Gsponer(*), J., Han(*), K. H., Jones(*), D. T., Longhi(*), S., Metallo(*), S. J., Nishikawa(*), K., Nussinov(*), R., Obradovic(*), Z., Pappu(*), R. V., Rost(*), B., Selenko, P., Subramaniam(*), V., Sussman(*), J. L., Tompa(*), P.; Uversky(*), V. N.
Intrinsically disordered proteins, 1:e24157
(2013)

Tags: In-Cell NMR (Selenko)

Abstract: "What's in a name? That which we call a rose By any other name would smell as sweet." From "Romeo and Juliet", William Shakespeare (1594) This article opens a series of publications on disambiguation of the basic terms used in the field of intrinsically disordered proteins. We start from the beginning, namely from the explanation of what the expression "intrinsically disordered protein" actually means and why this particular term has been chosen as the common denominator for this class of proteins characterized by broad structural, dynamic and functional characteristics.

Unraveling the existence of dynamic water channels in light-harvesting proteins: alpha-C-phycocyanobilin in vitro
Elgabarty(*), H., Schmieder, P.; Sebastiani(*), D.
Chem Sci, 4:755-763
(2013)

Tags: Solution NMR (Schmieder)

Abstract: We present hybrid ab initio QM/MM MD simulations and theoretical NMR chemical shift calculations of the bilin chromophore phycocyanobilin (PCB) in the binding pocket of the alpha-subunit of C-phycocyanin (alpha-C-PC). The good overall agreement between the computed NMR chemical shifts and the experimental values confirm the overall structural picture. A particular discrepancy is observed for the pyrrole nitrogen and hydrogen on ring A, which points to a disagreement between the reported X-ray structure and the experimental solution-state NMR spectrum. Our results suggest that in the solution-state, the binding pocket of alpha-C-PC slightly opens up allowing one water molecule to form a stable bridge between ring A in PCB and the protein backbone at the ASN73 residue. With this modified solution-state structure, the computed NMR chemical shifts are in excellent agreement with experimental values. For proteins still lacking a fully-resolved solution-state NMR-based structure, this approach of combining ab initio MD/NMR provides a very sensitive probe for local geometries at the sub-angstrom ngstrom range that can be utilized to compare/reconcile simple experimental one-and two-dimensional NMR data with X-ray structures.

Structural and biochemical characterization of Rv2140c, a phosphatidylethanolamine-binding protein from Mycobacterium tuberculosis
Eulenburg(*), G., Higman, V. A., Diehl, A., Wilmanns(*), M.; Holton(*), S. J.
Febs Letters, 587:2936-2942
(2013)

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: Rv2140c is one of many conserved Mycobacterium tuberculosis proteins for which no molecular function has been identified. We have determined a high-resolution crystal structure of the Rv2140c gene product, which reveals a dimeric complex that shares strong structural homology with the phosphatidylethanolamine-binding family of proteins. Rv2140c forms low-millimolar interactions with a selection of soluble phosphatidylethanolamine analogs, indicating that it has a role in lipid metabolism. Furthermore, the small molecule locostatin binds to the Rv2140c ligand-binding site and also inhibits the growth of the model organism Mycobacterium smegmatis. Structured digital abstract: Rv2140c and Rv2140c bind by molecular sieving (View interaction) v2140c and Rv2140c bind by cosedimentation in solution (View interaction) Rv2140c and Rv2140c bind by x-ray crystallography (View interaction) (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

Oligomerization of Dynamin Superfamily Proteins in Health and Disease
Faelber(*), K., Gao(*), S., Held(*), M., Posor, Y., Haucke, V., Noe(*), F.; Daumke(*), O.
Prog Mol Biol Transl, 117:411-443
(2013)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Proteins of the dynamin superfamily are mechanochemical GTPases, which mediate nucleotide-dependent membrane remodeling events. The founding member dynamin is recruited to the neck of clathrin-coated endocytic vesicles where it oligomerizes into helical filaments. Nucleotide-hydrolysis-induced conformational changes in the oligomer catalyze scission of the vesicle neck. Here, we review recent insights into structure, function, and oligomerization of dynamin superfamily proteins and their roles in human diseases. We describe in detail the molecular mechanisms how dynamin oligomerizes at membranes and introduce a model how oligomerization is linked to membrane fission. Finally, we discuss molecular mechanisms how mutations in dynamin could lead to the congenital diseases, Centronuclear Myopathy and Charcot-Marie Tooth disease.

Targeting Platelet G Protein-Coupled Receptors for Antithrombotic Therapy
Falker(*), K., Nazare, M., Wonerow(*), P.; Kozian(*), D. H.
Drug Develop Res, 74:440-449
(2013)

Tags: Medicinal Chemistry (Nazare)

Abstract: Platelets are small anucleated cells produced by bone marrow megakaryocytes that circulate in the blood as sentinels of vascular integrity. They play a pivotal role in the regulation of vascular homeostasis through adhesion to the injured vessel wall, aggregation, propagation of coagulation, and thrombus formation. Furthermore, platelets are also involved in fibrinolysis and the repair of the blood vessel wall, restoring blood flow and vascular integrity. Under pathophysiological conditions such as atherosclerosis, inappropriate platelet aggregation and clot formation can cause vascular occlusions, resulting in myocardial infarctions or stroke that, according to the World Health Organization, represent with more than 10% of worldwide death a major health risk (http://who.int/mediacentre/factsheets/fs310/en/). Over the last several decades, increasing efforts have been made to elucidate the cellular components, signaling pathways, and risk factors contributing to platelet activation with the main goal of providing a sound basis for the development of antiplatelet drugs and novel therapeutic treatment strategies. The family of seven transmembrane receptors, also designated G protein-coupled receptors (GPCRs), represented by approximately 800 members identified in the human genome represent the largest class of receptors and, hence, the richest source of targets for drug discovery. Here, we here provide an overview of the commonly applied therapies targeting platelet-GPCRs as well as a brief summary of novel approaches.

KSHV ORF67 encoded lytic protein localizes on the nuclear membrane and alters emerin distribution
Farina(*), A., Santarelli(*), R., Bloise(*), R., Gonnella(*), R., Granato(*), M., Bei(*), R., Modesti(*), A., Cirone(*), M., Bengtsson, L., Angeloni(*), A.; Faggioni(*), A.
Virus Res, 175:143-150
(2013)

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: p29, a newly identified Kaposi's sarcoma-associated herpesvirus (KSHV) protein, is the product of ORF67, the positional homolog of the conserved herpesvirus protein UL34. Like its homologues in other herpesviruses, p29 is expressed early during viral lytic cycle, and is localized on the nuclear rim. Upon chemical induction of viral replication in primary effusion lymphoma cells, p29 interacts with p33, encoded by ORF69, the positional homolog of the conserved herpesvirus protein UL31, and both proteins colocalize on the nuclear membrane. IFA and biochemical analysis of infected or transfected cells showed that p29 expression resulted in delocalization and hyperphosphorylation of emerin, whereas other nuclear lamin associated proteins, such as LUMA, LB1 and LBR were not affected. Mislocalization of emerin was robustly increased upon combined expression of p29 and p33, suggesting that emerin destabilization might represent the first step in nuclear lamina disassembling, a process necessary for nucleocapsid maturation. (C) 2013 Elsevier B.V. All rights reserved.

Culturing Primary Rat Inner Medullary Collecting Duct Cells
Faust(*), D., Geelhaar(*), A., Eisermann(*), B., Eichhorst, J., Wiesner, B., Rosenthal(*), W.; Klussmann(*), E.
Jove-J Vis Exp,
(2013)

Tags: Cellular Imaging (Wiesner)

Abstract: Arginine-vasopressin (AVP) facilitates water reabsorption by renal collecting duct principal cells and thereby fine-tunes body water homeostasis. AVP binds to vasopressin V2 receptors (V2R) on the surface of the cells and thereby induces synthesis of cAMP. This stimulates cellular signaling processes leading to changes in the phosphorylation of the water channel aquaporin-2 (AQP2). Protein kinase A phoshorylates AQP2 and thereby triggers the translocation of AQP2 from intracellular vesicles into the plasma membrane facilitating water reabsorption from primary urine. Aberrations of AVP release from the pituitary or AVP-activated signaling in principal cells can cause central or nephrogenic diabetes insipidus, respectively; an elevated blood plasma AVP level is associated with cardiovascular diseases such as chronic heart failure and the syndrome of inappropriate antidiuretic hormone secretion. Here, we present a protocol for cultivation of primary rat inner medullary collecting duct (IMCD) cells, which express V2R and AQP2 endogenously. The cells are suitable for elucidating molecular mechanisms underlying the control of AQP2 and thus to discover novel drug targets for the treatment of diseases associated with dysregulation of AVP-mediated water reabsorption. IMCD cells are obtained from rat renal inner medullae and are used for experiments six to eight days after seeding. IMCD cells can be cultured in regular cell culture dishes, flasks and micro-titer plates of different formats, the procedure only requires a few hours, and is appropriate for standard cell culture laboratories.

Alzheimer's Disease: Identification and Development of -Secretase (BACE-1) Binding Fragments and Inhibitors by Dynamic Ligation Screening (DLS)
Fernandez-Bachiller, M. I., Horatscheck, A., Lisurek, M.; Rademann, J.
Chemmedchem, 8:1041-1056
(2013)

Tags: Medicinal Chemistry (Rademann)

Abstract: The application of dynamic ligation screening (DLS), a methodology for fragment-based drug discovery (FBDD), to the aspartic protease -secretase (BACE-1) is reported. For this purpose, three new fluorescence resonance energy transfer (FRET) substrates were designed and synthesized. Their kinetic parameters (Vmax, KM, and kcat) were determined and compared with a commercial substrate. Secondly, a peptide aldehyde was designed as a chemically reactive inhibitor (CRI) based on the Swedish mutation substrate sequence. Incubation of this CRI with the protease, a FRET substrate, and one amine per well taken from an amine library, which was assembled by a maximum common substructure (MCS) approach, revealed the fragment 3-(3-aminophenyl)-2H-chromen-2-one (1) to be a competitive BACE-1 inhibitor that enhanced the activity of the CRI. Irreversibly formed fragment combination products of 1 with the initial peptide sequence were active and confirmed the targeting of the active site through the ethane-1,2-diamine isostere. Finally, structure-assisted combination of fragment 1 with secondary fragments that target the S1 site in hit optimization yielded novel, entirely fragment-based BACE-1 inhibitors with up to 30-fold improved binding affinity. Interactions with the protein were explained by molecular modeling studies, which indicate that the new fragment combinations interact with the catalytic aspartic acid dyad, as well as with the adjacent binding sites required for potency.

Page:  
Previous | 1, 2, 3, 4, 5, 6, ... , 9 | Next
Export as:
BibTeX, XML

Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)
info(at)fmp-berlin.de

Like many sites, we use cookies to optimize the user's browsing experience. Data Protection OK