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Redemann S.,Max Planck Institute of Molecular Cell Biology and Genetics | Schloissnig S.,European Molecular Biology Laboratory Heidelberg | Ernst S.,Max Planck Institute of Molecular Cell Biology and Genetics | Pozniakowsky A.,Max Planck Institute of Molecular Cell Biology and Genetics | And 3 more authors.
Nature Methods | Year: 2011

We present a method to control protein levels under native genetic regulation in Caenorhabditis elegans by using synthetic genes with adapted codons. We found that the force acting on the spindle in C. elegans embryos was related to the amount of the G-protein regulator GPR-1/2. Codon-adapted versions of any C. elegans gene can be designed using our web tool, C. elegans codon adapter. © 2011 Nature America, Inc. All rights reserved. Source


Wang Y.,Max Planck Institute of Psychiatry | Wang Y.,European Molecular Biology Laboratory Heidelberg | Kirschner A.,Max Planck Institute of Psychiatry | Fabian A.-K.,Max Planck Institute of Psychiatry | And 9 more authors.
Journal of Medicinal Chemistry | Year: 2013

The design of efficient ligands remains a key challenge in drug discovery. In the quest for lead-like ligands for the FK506-binding protein 51 (FKBP51), we designed two new classes of bicyclic sulfonamides to probe the contribution of conformational energy in these ligands. The [4.3.1] scaffold had consistently higher affinity compared to the [3.3.1] or monocyclic scaffolds, which could be attributed to better preorganization of two key recognition motifs. Surprisingly, the binding of the rigid [4.3.1] scaffold was enthalpy-driven and entropically disfavored compared to the flexible analogues. Cocrystal structures at atomic resolution revealed that the sulfonamide nitrogen in the bicyclic scaffolds can accept an unusual hydrogen bond from Tyr113 that mimics the putative FKBP transition state. This resulted in the first lead-like, functionally active ligand for FKBP51. Our work exemplifies how atom-efficient ligands can be achieved by careful conformational control even in very open and thus difficult binding sites such as FKBP51. © 2013 American Chemical Society. Source


Joosten R.P.,Netherlands Cancer Institute | Te Beek T.A.H.,Radboud University Nijmegen | Krieger E.,Radboud University Nijmegen | Hekkelman M.L.,Radboud University Nijmegen | And 4 more authors.
Nucleic Acids Research | Year: 2011

The Protein Data Bank (PDB) is the world-wide repository of macromolecular structure information. We present a series of databases that run parallel to the PDB. Each database holds one entry, if possible, for each PDB entry. DSSP holds the secondary structure of the proteins. PDBREPORT holds reports on the structure quality and lists errors. HSSP holds a multiple sequence alignment for all proteins. The PDBFINDER holds easy to parse summaries of the PDB file content, augmented with essentials from the other systems. PDB-REDO holds re-refined, and often improved, copies of all structures solved by X-ray. WHY NOT summarizes why certain files could not be produced. All these systems are updated weekly. The data sets can be used for the analysis of properties of protein structures in areas ranging from structural genomics, to cancer biology and protein design. © The Author(s) 2010. Source


Conrad C.,European Molecular Biology Laboratory Heidelberg | Gerlich D.W.,ETH Zurich
Journal of Cell Biology | Year: 2010

Fluorescence microscopy is one of the most powerful tools to investigate complex cellular processes such as cell division, cell motility, or intracellular trafficking. The availability of RNA interference (RNAi) technology and automated microscopy has opened the possibility to perform cellular imaging in functional genomics and other large-scale applications. Although imaging often dramatically increases the content of a screening assay, it poses new challenges to achieve accurate quantitative annotation and therefore needs to be carefully adjusted to the specific needs of individual screening applications. In this review, we discuss principles of assay design, large-scale RNAi, microscope automation, and computational data analysis. We highlight strategies for imaging-based RNAi screening adapted to different library and assay designs. © 2010 Conrad and Gerlich. Source


Thoma C.R.,ETH Zurich | Thoma C.R.,Brigham and Womens Hospital | Thoma C.R.,Harvard University | Matov A.,Scripps Research Institute | And 7 more authors.
Journal of Cell Biology | Year: 2010

Von Hippel-Lindau (VHL) tumor suppressor gene mutations predispose carriers to kidney cancer. The protein pVHL has been shown to interact with microtubules (MTs), which is critical to cilia maintenance and mitotic spindle orientation. However, the function for pVHL in the regulation of MT dynamics is unknown. We tracked MT growth via the plus end marker EB3 (end-binding protein 3)-GFP and inferred additional parameters of MT dynamics indirectly by spatiotemporal grouping of growth tracks from live cell imaging. Our data establish pVHL as a near-optimal MT-stabilizing protein: it attenuates tubulin turnover, both during MT growth and shrinkage, inhibits catastrophe, and enhances rescue frequencies. These functions are mediated, in part, by inhibition of tubulin guanosine triphosphatase activity in vitro and at MT plus ends and along the MT lattice in vivo. Mutants connected to the VHL cancer syndrome are differentially compromised in these activities. Thus, single cell-level analysis of pVHL MT regulatory function allows new predictions for genotype to phenotype associations that deviate from the coarser clinically defined mutant classifications. © 2010 Thoma et al. Source

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