147 research outputs found
Exploring the binding site of C-terminal Hsp90 inhibitors
No full textThe 90 kDa heat shock protein (Hsp90) is a prominent target for anticancer drug discovery. While its N-terminal domain has been widely exploited, several lines of evidence are emerging in favor of targeting its C-terminal domain to conceive innovative drugs based on perturbation of the dimer interface. Here, we describe the application of several computational approaches useful to predict the location of the C-terminal binding site
A computational workflow for the design of irreversible inhibitors of protein kinases
No full textDesign of irreversible inhibitors is an emerging and relatively less explored strategy for the design of protein kinase inhibitors. In this paper, we present a computational approach for the creation of a database of already known reversible inhibitors of protein kinases, the selection of the most promising scaffolds that bind one or more desired kinase templates, the modification of the scaffolds by introduction of chemically reactive groups (suitable cysteine traps) and the final evaluation of the reversible and irreversible protein–ligand. The workflow was tested on a database of known inhibitors of ERK2, a protein kinase possessing a cysteine in the ATP site
Improving the quality of protein NMR structures by Rosetta refinement and its application in molecular replacement
No full textThis dissertation demonstrates restrained Rosetta refinement can improve the quality of protein NMR structures and describes a protocol to improve their phasing power. Recent studies manifest unrestrained Rosetta refinement can improve the stereochemical quality and geometry of protein NMR structures, to move NMR structures closer to their X-ray counterparts and consequently to improve their phasing power in a few cases. In this study, we intend to explore whether those observations stand corrected in general and the impact of incorporating NMR experimental restraints into Rosetta refinement. We developed a newer version of PdbStat software to convert Cyana/Xplor formatted restraints into Rosetta formatted restraints. Based on a dataset of 41 NESG NMR/X-ray structure pairs, we have done unrestrained and restrained Rosetta refinement for all the NMR structures. The knowledge based structural quality Z-scores are significantly improved by Rosetta refinement with or without restraints. Compared with unrestrained Rosetta refined structures, restrained Rosetta refined structures fit the experimental data better, are in better agreement with their X-ray counterparts and are generally of better phasing power, while unrestrained Rosetta refinement often drives the NMR structures further from their X-ray counterparts especially when the structural similarity between NMR structures and X-ray structures is high. To summarize, a majority of the experimental NMR restraints still apply for X-ray crystal structures determined at crystalline environment, and they can be utilized to guide Rosetta refinement to improve the quality of NMR structures. Molecular replacement (MR) is widely used for addressing the phase problem in X-ray crystallography. Historically, crystallographers have had limited success using NMR structures as MR search models. Here, we report a comprehensive investigation of the utility of protein NMR structures as MR search models, using a dataset of 25 NESG NMR/X-ray structure pairs. Starting from NMR ensembles prepared by an improved protocol, FindCore, correct MR solutions were obtained for 22 targets. Rosetta refinement of NMR structures provided MR solutions for another two proteins. We also demonstrate that such properly prepared NMR ensembles and X-ray crystal structures have similar performance when used as MR search models for homologous structures, particularly for targets with sequence identity >40%.Ph. D.Includes bibliographical referencesIncludes vitaby Binchen Ma
An introduction to comets: post-Rosetta perspectives
No full textWritten by a leading expert on comets, this textbook is divided into seven main elements with a view to allowing advanced students to appreciate the interconnections between the different elements. The author opens with a brief introductory segment on the motivation for studying comets and the overall scope of the book. The first chapter describes fundamental aspects most usually addressed by ground-based observation. The author then looks at the basic physical phenomena in four separate chapters addressing the nucleus, the emitted gas, the emitted dust, and the solar wind interaction. Each chapter introduces the basic physics and chemistry but then new specific measurements by Rosetta instruments at comet Churyumov-Gerasimenko are brought in. A concerted effort has been made to distinguish between established fact and conjecture. Deviations and inconsistencies are brought out and their significance explained. Links to previous observations of comets Tempel 1, Wild 2, Hartley 2, Halley and others are made. The author then closes with three smaller chapters on related objects, the loss of comets, and prospects for future exploration. This textbook includes over 275 graphics and figures – most of which are original. Thorough explanations and derivations are included throughout the chapters. The text is therefore designed to support MSc. students and new PhD students in the field wanting to gain a solid overview of the state-of-the-art
Discovery and study of Comet 67P/Churyumov−Gerasimenko, the main target of the Rosetta space mission
No full textRosetta, a European space vehicle, which was 15 years in development, headed for short-period Comet 67P/Churyumov–Gerasimenko in February 2004. In September 1969 S. Gerasimenko and the author went to the Alma-Ata Astrophysical Institute to carry out a survey of short-period and new comets. At a later date of that month, the author examined the exposure of Comet 32P/Comas Sola made on September 11.92 UT, 1969 and found a cometary object near the plate centre. The author assumed it to be the expected short-period Comet 32P/Comas Sola. Later explorations at the Kyiv University revealed that this comet’s position differed from predicted calculations for Comet 32P by 1.8°. It was a new comet. The comet had an apparent magnitude of 13 and the faint tail about 1 arcmin in length at a position angle of 280°. On the basis of the observations of Comet 67P obtained in Nizhny Arkhyz with the help of the 6-m BTA reflector of the SAO RAS, some physical parameters of the cometary plasma tail (coefficients of diffusion D||, D┴ and induction of magnetic field B) were determined (Jan. 12.105 UT, 1983: D|| = (5.07 · 10¹⁴ – 1.21 · 10¹⁵) cm²/s, D┴ = (5.73 · 10¹³ − 1.37 · 10¹⁴) cm²/s, B = (46 − 111) nT; Jan. 13.124 UT, 1983: D|| = (4.67 · 10¹⁴ – 1.14 ·10¹⁵) cm²/s, D┴ = (4.30 ·10¹³−1.05 ·10¹⁴) cm²/s, B = (55 − 134) nT). The author hope that the Rosetta space mission will obtain valuable data for solving the fundamental scientific problem on the origin and evolution history of the Solar System.The work was partially supported by the Fundamental Research State Fund of the Ministry of Ukraine for Education and Science (grant 2002)
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No full textThe origin of animal multicellularity may be reconstructed by comparing animals with one of their closest living relatives, the choanoflagellate Salpingoeca rosetta. Just as animals develop from a single cell-the zygote-multicellular rosettes of S. rosetta develop from a founding cell. To investigate rosette development, we established forward genetics in S. rosetta. We find that the rosette defect of one mutant, named Rosetteless, maps to a predicted C-type lectin, a class of signaling and adhesion genes required for the development and innate immunity in animals. Rosetteless protein is essential for rosette development and forms an extracellular layer that coats and connects the basal poles of each cell in rosettes. This study provides the first link between genotype and phenotype in choanoflagellates and raises the possibility that a protein with C-type lectin-like domains regulated development in the last common ancestor of choanoflagellates and animals
Relationships of oral reading and word recognition abilities of first grade pupils to their performances on tests of rate and accuracy of perception
No full textINVESTIGATING MECHANISMS OF TRANSIENT RECEPTOR POTENTIAL REGULATION WITH NUCLEAR MAGNETIC RESONANCE AND ROSETTA COMPUTATIONAL BIOLOGY
No full textabstract: The physiological phenomenon of sensing temperature is detected by transient
receptor (TRP) ion channels, which are pore forming proteins that reside in the
membrane bilayer. The cold and hot sensing TRP channels named TRPV1 and TRPM8
respectively, can be modulated by diverse stimuli and are finely tuned by proteins and
lipids. PIRT (phosphoinositide interacting regulator of TRP channels) is a small
membrane protein that modifies TRPV1 responses to heat and TRPM8 responses to cold.
In this dissertation, the first direct measurements between PIRT and TRPM8 are
quantified with nuclear magnetic resonance and microscale thermophoresis. Using
Rosetta computational biology, TRPM8 is modeled with a regulatory, and functionally
essential, lipid named PIP2. Furthermore, a PIRT ligand screen identified several novel
small molecular binders for PIRT as well a protein named calmodulin. The ligand
screening results implicate PIRT in diverse physiological functions. Additionally, sparse
NMR data and state of the art Rosetta protocols were used to experimentally guide PIRT
structure predictions. Finally, the mechanism of thermosensing from the evolutionarily
conserved sensing domain of TRPV1 was investigated using NMR. The body of work
presented herein advances the understanding of thermosensing and TRP channel function
with TRP channel regulatory implications for PIRT.Dissertation/ThesisDoctoral Dissertation Biochemistry 201
The effectiveness of reducing stress through the use of relaxation therapy for the spouse of a stroke patient, 1995
No full textThis study examined the effects of using relaxation therapy on a spouse of a stroke patient to provide a way of reducing stress. The purpose of this study was to reduce stress in a caregiver of a spouse. The subnect of this study was a black woman who was monitored for 12 weeks concluded by a follow-up home visit. The instrument used in the study was a 25 item, self administered questionnaire which was adapted from The WALMYR Assessment Scales Scoring Manual by W. W. Hudson entitled Index of Clinical Stress (ICS). The analysis was completed utilizing the Statistical Package for the Social Sciences X (SPSSX). The crisis intervention theory was applied to cushion the impact of the stressful event by offering immediate emotional aid and by strengthening the client's coping ability. The results showed the level of stress in the participant did decrease after intervention
What are the community resources available for use in the elementary schools of Birmingham, Alabama, 1955-1956, 1956
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