1,720,982 research outputs found
The ABC of protein kinase conformations
No full textConformation plays a crucial role in kinase biology. In this paper, we present a ternary classification scheme of the structural kinome based on the conformation of the DFG-motif (DFG-F and DFG-G side chain torsion) and the displacement of aC-helix and DFG, revealing a small set of major conformations. The DFG-motif occurs in three eclipsed conformations which differ in propensity for aC-helix displacement. The tight interaction between aC-helix and DFG forms a strong bias towards the active conformation and organizes the universal features of active kinases. The activating effect of sequence, phosphorylation, cyclin and inhibitor binding can be estimated by thermodynamic analyses. A likely path for the DFG-out transition, rotation around the bond between DFG-1 and DFG-F after a backbone flip, is suggested by its population in the pdb. Consistent with this mechanism, flexible, lipophilic residues in the path of the DFG-F sidechain and flexibility of aC-helix are required for the transition. Displacement of aC-helix involves subtle shifts in improper torsion angles which propagate to a bending of the C-terminal loop between aC-helix and the HPN motif
Design principles for balanced lipophilicity and permeability in beyond Rule of 5 space
No full textA conformational analysis of all oral bRo5 drugs using a QM-based workflow and experimental structures revealed similar polar surface area (PSA) thresholds as for Ro5 drugs and a modest impact of environments on 3D-PSA and intramolecular hydrogen bond (IMHB) count (often termed chameleonicity) despite a significant difference between TPSA and 3D PSA. The minimum TPSA-3D PSA to maintain permeability in bRo5 space depends on the fraction of polarity (TPSA/MW). TPSA/MW in the bRo5 and Ro5 oral drugs sets had a median of ~0.2 Å2/Da, with the upper half corresponding to the upper decile of logP 100 Å2 de-fines the sweet spot of this "rule of 1/5" occupied by the majority of oral bRo5 drugs. TPSA-3DPSA increased in the lead optimization (LO) campaigns of three first in class de novo designed bRo5 drugs and may be a useful parameter for future bRo5 LO campaigns
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Mutational analysis of isoform selectivity and conformational equilibria in protein kinase inhibition
Get PDFDeregulation of protein kinases is associated with many diseases making them important targets for therapeutic intervention. Kinases can switch between active and inactive conformations that can be targeted by type 1 or type 2 inhibitors respectively. One of the most relevant conformational switches is the ‘in’ and ‘out’ movement of the ATP/Mg2+ binding motif DFG. Factors modulating the conformational equilibria such as the residue environment of regulatory motifs remain poorly understood despite their importance for drug discovery. In this thesis, the first model system tested the hypothesis that accessibility of the DFG-out conformation is restricted by the energetic cost of transition between the in and out states. CDK2 was chosen as a target that was thought to have an inaccessible DFG-out conformation, and several point mutations were introduced to promote this conformational transition. Detailed biochemical and biophysical characterisation illustrated that the mutants bound type 2 inhibitors more potently than the wild type. In addition, the wild-type CDK2 was shown to bind type 2 inhibitors in the absence, but not in the presence, of cyclin. The first known CDK2 co-crystal structure in the DFG-out conformation was solved, opening the door to a new class of CDK2 inhibitors. In the second project, site-directed mutagenesis was used to explore the residues determining inhibitor selectivity between PIM1 and PIM2. Evaluation of ligand binding to the variants and comparison of PIM1 and PIM2 crystal structures showed that flexibility of the phosphate-binding loop was the dominant factor determining the differences in their affinities for ATP and small molecule inhibitors. These studies illustrate that residues contributing to kinase conformational equilibria can be just as important for inhibitor binding as contact residues formed in the ligand complex
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