2,351 research outputs found
Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen
No full textThe adaptor protein Grb2 links cell-surface receptors, such as Her2, to the multisite docking proteins Gab1 and 2, leading to cell growth and proliferation in breast and other cancers. Gab2 interacts with the C-terminal SH3 domain (SH3C) of Grb2 through atypical RxxK motifs within polyproline II or 3 10 helices. A virtual screen was conducted for putative binders of the Grb2 SH3C domain. Of the top hits, 34 were validated experimentally by surface plasmon resonance spectroscopy and isothermal titration calorimetry. A subset of these molecules was found to inhibit the Grb2-Gab2 interaction in a competition assay, with moderate to low affinities (5: IC50 320 μM). The most promising binders were based on a dihydro-s-triazine scaffold, and are the first small molecules reported to target the Grb2 SH3C protein-interaction surface. © 2013 Elsevier Ltd. All rights reserved
A Polyproline Type II Peptidomimetic Disrupts a Grb2 SH3C Domain Protein–Protein Interaction Implicated in Breast Cancer
No full textGiven the essential role of protein–protein interactions (PPIs) in cellular signaling pathways, their selective modulation is of great therapeutic interest. Mimicry of secondary structural protein elements has emerged as a promising strategy, with various scaffolds reproducing recognition surfaces of α–helical and β–strand/sheet proteins. A critical PPI, controlling cell growth and proliferation in breast and other cancers, occurs between growth factor receptor‐bound protein 2 (Grb2) and a polyproline II (PPII) helix embedded in Gab2. Herein, the first example of a general approach for nonpeptidic mimicry of extended PPII helices is presented and it is demonstrated that the scaffold may be functionalized to recapitulate the binding characteristics of crucial hydrophobic and cationic Gab2 hot‐spot side‐chains. The rationally designed peptidomimetic binds Grb2 at the same position as Gab2 (protein‐observed nuclear magnetic resonance (NMR)) with affinities comparable to the native peptide sequence (surface plasmon resonance (SPR)). With the addition of a new PPII minimalist scaffold, these studies further validate the use of diverse secondary structure peptidomimetics in disrupting therapeutically relevant PPIs
Bad Astronomy
No full textThis web site is devoted to airing out myths and common misconceptions about astronomy and related topics. There is also a blog which the author, who is an astronomer, often posts to
Motion and mobility in the realist novels of Philip K Dick
No full textThis essay explores the ways that ideas of motion and mobility support readings of Philip K Dick's early novels that take full account of the changing geographical context. They are set during a period of rapid suburban expansion, the building of the interstate and the spread of automobility through car ownership, and their characters frequently exist in a state between continuity through conformity and the potential for change. The open ended forms of the novels reflect a world around Dick that was still under construction, and where alternative realities can be glimpsed between incomplete materialities
An analysis of the correspondence and hagiographical works of Philip of Harvengt
No full textFor every famous author of the twelfth-century renaissance, there are numerous lesser-known writers. Despite being overshadowed by more brilliant scholars or those closer to the centre of important events, their voices add depth to the study of the intellectual history of this period. A founding member of one of the earliest Premonstratensian houses; a highly-educated and prolific author, much in demand as a hagiographer; and a vigorous defender of the clerical order, Philip of Harvengt is one such writer, and a worthy subject for study. This thesis examines two bodies of Philip’s works – his letters and his hagiographical writings – analysing the predominant and recurrent concerns and ideals expressed in them, and the means by which they are expressed.
The letters are carefully crafted works, examples of the literary labour which Philip writes is incumbent upon the cleric. The first part of this thesis approaches these letters in chapters on four themes: the role of the ecclesiastical prelate; the importance of learning; the relationship between religious orders; and Philip’s use of the motif of friendship. His hagiographical works, too, are examples of literary artistry, to move as well as to educate the audience. In the second part of the thesis, these will be discussed individually, with the first chapter analysing his vita of Oda, a nun attached to his own house, whom he portrays as a martyr. The succeeding chapters consider Philip’s rewritings of earlier vitae, and show how he managed his sources in order to produce vitae depicting their subjects according to his ideal model of sanctity.
Philip’s letters express concerns shared by contemporaries, reflecting anxieties surrounding roles and ideal forms of living in a period immediately following the first fervour of religious renewal. His hagiographies articulate ideals of sanctity, clarifying these when they are not made sufficiently explicit in earlier works, for the better edification of an audience pursuing this vita perfecta. Both letters and hagiographies are designed to exhort and instruct the reader or listener: above all, Philip is a teacher
On Philip Pullman’s fantastic politics and The Book of Dust
No full textFirst paragraph: Millions have been thrilled to hear that His Dark Materials author Philip Pullman is back with the long-awaited follow-up to the infamous trilogy. The Book of Dust had been referred to as early as the publication of The Amber Spyglass in 2000, but at last the first in a new trilogy is confirmed for publication in October. Pre-orders have already propelled the first title to the top of the bestseller lists, and speculation is running riot
Increasing transparency in the British Journal of Nutrition
No full textKeen readers of the BJN will have noticed the recent appearance of ‘conflict of interest’ statements and of more complete descriptions of the contribution of each author to the publication. I have introduced these innovations in order to increase the transparency of the articles that we publish in the BJN; further strategies to increase accuracy, transparency and accountability of papers published in the journal will follow in order to encourage a climate of intellectual honesty and to decrease the risk of misconduct. In particular, the journal will follow as closely as possible the recommendations and guidelines of the Committee on Publishing Ethics (COPE)(1) and of the International Committee of Medical Journal Editors (ICMJE)(2). COPE and ICMJE have made available a range of guidelines aimed at establishing best practice in scientific publishing. These include guidelines for authors and for the conduct of reviewers, editorial boards and editors. Many of the guidelines are already followed by the BJN, but others are not yet fully in place
When do special interests run rampant ? disentangling the role in banking crises of elections, incomplete information, and checks and balances
No full textThe author investigates the political determinants of government decisions that benefit special interest groups - especially government decisions to deal with banking crises. He finds that the better informed the voters, the more proximate elections, and the larger the number of political veto players ( conditional on the costs to voters of relevant policy decision), the smaller the government's fiscal transfer are to the financial sector and the less likely the government is to exercise forbearance in dealing with insolvent financial institutions. The results suggest that policies thatmight be appropriate for mitigating banking crises in the United States might be less effective in settings where voters are less informed, where elections are less competitive, and where there are fewer veto players, because in these settings checks and balances are missing. These policies include: a) Disseminating information about the costs of inefficient government decisions. b) Improving the structure of legislative regulatory oversight. c) Intervening early in insolvent banks. The author concludes that the more veto players there are, the less likely policies are to favor special interest groups (contrary to previous views). Moreover, the closer the elections, the less likely policies are to favor special interest groups.
Conformational Recognition of an Intrinsically Disordered Protein
No full textAbstractThere is a growing interest in understanding the properties of intrinsically disordered proteins (IDPs); however, the characterization of these states remains an open challenge. IDPs appear to have functional roles that diverge from those of folded proteins and revolve around their ability to act as hubs for protein-protein interactions. To gain a better understanding of the modes of binding of IDPs, we combined statistical mechanics, calorimetry, and NMR spectroscopy to investigate the recognition and binding of a fragment from the disordered protein Gab2 by the growth factor receptor-bound protein 2 (Grb2), a key interaction for normal cell signaling and cancer development. Structural ensemble refinement by NMR chemical shifts, thermodynamics measurements, and analysis of point mutations indicated that the population of preexisting bound conformations in the free-state ensemble of Gab2 is an essential determinant for recognition and binding by Grb2. A key role was found for transient polyproline II (PPII) structures and extended conformations. Our findings are likely to have very general implications for the biological behavior of IDPs in light of the evidence that a large fraction of these proteins possess a specific propensity to form PPII and to adopt conformations that are more extended than the typical random-coil states
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