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Understanding the physical attributes of protein‐ligand interfaces, the source of most biological activity, is a fundamental problem in biophysics. Knowing the characteristic features of interfaces also enables the design of molecules with potent and selective interactions. Prediction of native protein‐ligand interactions has traditionally focused on the development of physics‐based potential energy functions, empirical scoring functions that are fit to binding data, and knowledge‐based potentials that assess the likelihood of pairwise interactions. Here we explore a new approach, testing the hypothesis that protein‐ligand binding results in computationally detectable rigidification of the protein‐ligand interface. Our SiteInterlock approach uses rigidity theory to efficiently measure the relative interfacial rigidity of a series of small‐molecule ligand orientations and conformations for a number of protein complexes. In the majority of cases, SiteInterlock detects a near‐native binding mode as being the most rigid, with particularly robust performance relative to other methods when the ligand‐free conformation of the protein is provided. The interfacial rigidification of both the protein and ligand prove to be important characteristics of the native binding mode. This measure of rigidity is also sensitive to the spatial coupling of interactions and bond‐rotational degrees of freedom in the interface. While the predictive performance of SiteInterlock is competitive with the best of the five other scoring functions tested, its measure of rigidity encompasses cooperative rather than just additive binding interactions, providing novel information for detecting native‐like complexes. SiteInterlock shows special strength in enhancing the prediction of native complexes by ruling out inaccurate poses. Proteins 2016; 84:1888–1901. © 2016 Wiley Periodicals, Inc. 相似文献
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Ivonne Gamper David Fleck Meltem Barlin Marc Spehr Sara El Sayad Henning Kleine Sebastian Maxeiner Carmen Schalla Gülcan Aydin Mareike Hoss David W. Litchfield Bernhard Lüscher Martin Zenke Antonio Sechi 《Molecular biology of the cell》2016,27(2):277-294
Spatiotemporal cytoskeleton remodeling is pivotal for cell adhesion and migration. Here we investigated the function of Gas2-related protein on chromosome 22 (GAR22β), a poorly characterized protein that interacts with actin and microtubules. Primary and immortalized GAR22β−/− Sertoli cells moved faster than wild-type cells. In addition, GAR22β−/− cells showed a more prominent focal adhesion turnover. GAR22β overexpression or its reexpression in GAR22β−/− cells reduced cell motility and focal adhesion turnover. GAR22β–actin interaction was stronger than GAR22β–microtubule interaction, resulting in GAR22β localization and dynamics that mirrored those of the actin cytoskeleton. Mechanistically, GAR22β interacted with the regulator of microtubule dynamics end-binding protein 1 (EB1) via a novel noncanonical amino acid sequence, and this GAR22β–EB1 interaction was required for the ability of GAR22β to modulate cell motility. We found that GAR22β is highly expressed in mouse testes, and its absence resulted in reduced spermatozoa generation, lower actin levels in testes, and impaired motility and ultrastructural disorganization of spermatozoa. Collectively our findings identify GAR22β as a novel regulator of cell adhesion and migration and provide a foundation for understanding the molecular basis of diverse cytoskeleton-dependent processes. 相似文献
175.
Qingzhi An Qing Sun Andreas Weu David Becker‐Koch Fabian Paulus Sebastian Arndt Fabian Stuck A. Stephen K. Hashmi Nir Tessler Yana Vaynzof 《Liver Transplantation》2019,9(33)
Four π‐extended phosphoniumfluorene electrolytes (π‐PFEs) are introduced as hole‐blocking layers (HBL) in inverted architecture planar perovskite solar cells with the structure of ITO/PEDOT:PSS/MAPbI3/PCBM/HBL/Ag. The deep‐lying highest occupied molecular orbital energy level of the π‐PFEs effectively blocks holes, decreasing contact recombination. It is demonstrated that the incorporation of π‐PFEs introduces a dipole moment at the PCBM/Ag interface, resulting in significant enhancement of the built‐in potential of the device. This enhancement results in an increase in the open‐circuit voltage of the device by up to 120 mV, when compared to the commonly used bathocuproine HBL. The results are confirmed both experimentally and by numerical simulation. This work demonstrates that interfacial engineering of the transport layer/contact interface by small molecule electrolytes is a promising route to suppress nonradiative recombination in perovskite devices and compensates for a nonideal energetic alignment at the hole‐transport layer/perovskite interface. 相似文献
176.
Sebastian Weber Sebastian Schaepe Stephan Freyer Michael‐Helmut Kopf Christian Dietzsch 《Engineering in Life Science》2019,19(3):159-167
Jet aerated loop reactors (JLRs) provide high mass transfer coefficients (kLa) and can be used for the intensification of mass transfer limited reactions. The jet loop reactor achieves higher kLa values than a stirred tank reactor (STR). The improvement relies on significantly higher local power inputs (~104) than those obtainable with the STR. Operation at high local turnover rates requires efficient macromixing, otherwise reactor inhomogeneities might occur. If sufficient homogenization is not achieved, the selectivity of the reaction and the respective yields are decreased. Therefore, the balance between mixing and mass transfer in jet loop reactors is a critical design aspect. Monitoring the dissolved oxygen levels during the turnover of a steady sodium sulfite feed implied the abundance of gradients in the JLR. Prolonged mixing times at identical power input and aeration rates (~100%) were identified for the JLR in comparison to the STR. The insertion of a draft tube to the JLR led to a more homogenous dissolved oxygen distribution, but unfortunately a reduction of mixing time was not achieved. In case of increased medium viscosities as they may arise in high cell density cultivations, no gradient formation was detected. However, differences in medium viscosity significantly altered the mass transfer and mixing performance of the JLR. 相似文献
177.
Sebastian Tesche Ren Rsemeier‐Scheumann Jonas Lohr Ren Hanke Jochen Büchs Rainer Krull 《Engineering in Life Science》2019,19(11):781-794
Salt‐enhanced cultivation as a morphology engineering tool for the filamentous actinomycete Actinomadura namibiensis was evaluated in 500‐mL shaking flasks (working volume 100 mL) with the aim of increasing the concentration of the pharmaceutically interesting peptide labyrinthopeptin A1. Among the inorganic salts added to a complex production medium, the addition of (NH4)2SO4 led to the highest amount of labyrinthopeptin A1 production. By using 50 mM (NH4)2SO4, the labyrinthopeptin A1 concentration increased up to sevenfold compared to the non‐supplemented control, resulting in 325 mg L?1 labyrinthopeptin A1 after 10 days of cultivation. The performance of other ammonium‐ and sulfate‐containing salts (e.g., NH4Cl, K2SO4) was much lower than the performance of (NH4)2SO4. A positive correlation between the uptake of glycerol as one of the main carbon sources and nongrowth‐associated labyrinthopeptin productivity was found. The change in the cell morphology of A. namibiensis in conjunction with increased osmolality by the addition of 50 mM (NH4)2SO4, was quantified by image analysis. A. namibiensis always developed a heterogeneous morphology with pellets and loose mycelia present simultaneously. In contrast to the non‐supplemented control, the morphology of (NH4)2SO4‐supplemented cultures was characterized by smaller and circular pellets that were more stable against disintegration in the stationary production phase. 相似文献
178.
Neylen Del Toro Ana Fernandez-Ruiz Lian Mignacca Paloma Kalegari Marie-Camille Rowell Sebastian Igelmann 《Cell cycle (Georgetown, Tex.)》2019,18(6-7):759-770
Senescence is a tumor suppressor program characterized by a stable growth arrest while maintaining cell viability. Senescence-associated ribogenesis defects (SARD) have been shown to regulate senescence through the ability of the ribosomal protein S14 (RPS14 or uS11) to bind and inhibit the cyclin-dependent kinase 4 (CDK4). Here we report another ribosomal protein that binds and inhibits CDK4 in senescent cells: L22 (RPL22 or eL22). Enforcing the expression of RPL22/eL22 is sufficient to induce an RB and p53-dependent cellular senescent phenotype in human fibroblasts. Mechanistically, RPL22/eL22 can interact with and inhibit CDK4-Cyclin D1 to decrease RB phosphorylation both in vitro and in cells. Briefly, we show that ribosome-free RPL22/eL22 causes a cell cycle arrest which could be relevant during situations of nucleolar stress such as cellular senescence or the response to cancer chemotherapy. 相似文献
179.
The genus Olpidiopsis of the Oomycota includes several species that are aquatic parasites and hyperparasites. Despite their widespread occurrence and potential ecological importance, only a handful of these species has been subjected to phylogenetic investigations, so far. Most species have not been observed and reported for several decades. In the current study, the freshwater diatom parasite Olpidiopsis gillii (de Wild.) Friedmann was rediscovered from the river Main in Germany and investigated for its phylogenetic placement using nuclear small ribosomal subunit (SSU) sequences. The absence of a zoospore diplanetism is a characteristic of the genus Olpidiopsis, which is in contrast to the diplanetism observed in species of Ectrogella. The phylogenetic reconstruction revealed that Olpidiopsis gillii is a basal lineage within the oomycetes, grouping together with the recently-described marine diatom parasite Olpidiopsis drebesii with high support, and loosely associated with Olpidiopsis species parasitising red algae. However, as there are no sequence data available for the type species of both Olpidiopsis and Ectrogella the taxonomic assignment of these simple holocarpic parasites of algae and diatoms remains fraught with uncertainty. 相似文献
180.