scholarly journals Towards Unraveling the Histone Code by Fragment Blind Docking

2019 ◽  
Vol 20 (2) ◽  
pp. 422 ◽  
Author(s):  
Mónika Bálint ◽  
István Horváth ◽  
Nikolett Mészáros ◽  
Csaba Hetényi
Keyword(s):  
Binding Sites ◽  
Histone Code ◽  
New Drugs ◽  
Post Translational Modifications ◽  
New Approach ◽  
Docking Method ◽  
Peptide Conformations ◽  
Experimental Structure ◽  
Fragment Docking

Histones serve as protein spools for winding the DNA in the nucleosome. High variability of their post-translational modifications result in a unique code system often responsible for the pathomechanisms of epigenetics-based diseases. Decoding is performed by reader proteins via complex formation with the N-terminal peptide tails of histones. Determination of structures of histone-reader complexes would be a key to unravel the histone code and the design of new drugs. However, the large number of possible histone complex variations imposes a true challenge for experimental structure determination techniques. Calculation of such complexes is difficult due to considerable size and flexibility of peptides and the shallow binding surfaces of the readers. Moreover, location of the binding sites is often unknown, which requires a blind docking search over the entire surface of the target protein. To accelerate the work in this field, a new approach is presented for prediction of the structure of histone H3 peptide tails docked to their targets. Using a fragmenting protocol and a systematic blind docking method, a collection of well-positioned fragments of the H3 peptide is produced. After linking the fragments, reconstitution of anchoring regions of the target-bound H3 peptide conformations was possible. As a first attempt of combination of blind and fragment docking approaches, our new method is named fragment blind docking (FBD).

Conformation of Ribosomes from Escherichia Coli

1974 ◽  
Vol 32 ◽  
pp. 210-211
Author(s):  
M. Boublik ◽  
W. Hellmann ◽  
F. Jenkins
Keyword(s):  
Binding Sites ◽  
Ribosomal Proteins ◽  
Fluorescent Dyes ◽  
Protein Biosynthesis ◽  
Three Dimensional ◽  
Spatial Arrangement ◽  
Dimensional Structure ◽  
Complete Understanding ◽  
And Function

The present knowledge of the three-dimensional structure of ribosomes is far too limited to enable a complete understanding of the various roles which ribosomes play in protein biosynthesis. The spatial arrangement of proteins and ribonuclec acids in ribosomes can be analysed in many ways. Determination of binding sites for individual proteins on ribonuclec acid and locations of the mutual positions of proteins on the ribosome using labeling with fluorescent dyes, cross-linking reagents, neutron-diffraction or antibodies against ribosomal proteins seem to be most successful approaches. Structure and function of ribosomes can be correlated be depleting the complete ribosomes of some proteins to the functionally inactive core and by subsequent partial reconstitution in order to regain active ribosomal particles.

The Dudley Lee Case: A new approach to factual causation and its implications for transformative jurisprudence

2017 ◽  
Vol 30 (1) ◽  
pp. 273-289
Author(s):  
Anmari Meerkotter
Keyword(s):  
Case Note ◽  
Constitutional Court ◽  
Recent Contribution ◽  
New Approach ◽  
State Accountability ◽  
The Law ◽  
Transformative Impact ◽  
Constitutional Jurisprudence ◽  
Law Of Delict

The Constitutional Court (CC) judgment of Lee v Minister of Correction Services 2013 2SA 144 (CC) is a recent contribution to transformative constitutional jurisprudence in the field of the law of delict. This matter turned on the issue of factual causation in the context of wrongful and negligent systemic omissions by the state. In this case note, I explore the law relating to this element of delictual liability with specific regard to the traditional test for factual causation – the conditio sine qua non (‘but-for’) test. In particular, I note the problems occasioned by formalistic adherence to this test in the context of systemic state omissions as evidenced by the SCA judgment in the same matter. I also consider the manner in which English courts have addressed this problem. Thereafter, I analyse the CC’s broader approach to the determination of factual causation as one based on common sense and justice. I argue that this approach endorses a break from a formalistic application of the test and constitutes a step towards an approach which resonates with the foundational constitutional values of freedom, dignity and equality. Furthermore, it presents an appropriate solution to the problems associated with factual causation where systemic omissions are concerned. I then consider the transformative impact of the Lee judgment. In particular, I argue that the broader enquiry favoured by the CC facilitates the realisation of constitutionally guaranteed state accountability, and amounts to an extension of the existing norm of accountability jurisprudence. Hence, I contend that the judgment presents a further effort by the Constitutional Court to effect wholesale the constitutionalisation of the law of delict, as well as a vindicatory tool to be used by litigants who have been adversely affected by systemic state omissions.

Automatic Determination of Optimal FIB Operations for Improved Circuit Probing and Fast Reconfiguration

2000 ◽  
Author(s):  
Romain Desplats ◽  
Timothee Dargnies ◽  
Jean-Christophe Courrege ◽  
Philippe Perdu ◽  
Jean-Louis Noullet
Keyword(s):  
Integrated Circuit ◽  
Focused Ion Beam ◽  
Ion Beam ◽  
Semiconductor Devices ◽  
Front Side ◽  
Automatic Determination ◽  
Metal Line ◽  
New Approach ◽  
Metal Layers

Abstract Focused Ion Beam (FIB) tools are widely used for Integrated Circuit (IC) debug and repair. With the increasing density of recent semiconductor devices, FIB operations are increasingly challenged, requiring access through 4 or more metal layers to reach a metal line of interest. In some cases, accessibility from the front side, through these metal layers, is so limited that backside FIB operations appear to be the most appropriate approach. The questions to be resolved before starting frontside or backside FIB operations on a device are: 1. Is it do-able, are the metal lines accessible? 2. What is the optimal positioning (e.g. accessing a metal 2 line is much faster and easier than digging down to a metal 6 line)? (for the backside) 3. What risk, time and cost are involved in FIB operations? In this paper, we will present a new approach, which allows the FIB user or designer to calculate the optimal FIB operation for debug and IC repair. It automatically selects the fastest and easiest milling and deposition FIB operations.

GABAA receptors: Various stoichiometrics of subunit arrangement in α1β3 and α1β3ε receptors

2018 ◽  
Vol 24 (17) ◽  
pp. 1839-1844 ◽  
Author(s):  
Ahmad Tarmizi Che Has ◽  
Mary Chebib
Keyword(s):  
Central Nervous System ◽  
Gabaa Receptors ◽  
Binding Sites ◽  
New Drugs ◽  
Pharmacological Properties ◽  
Receptor Complex ◽  
The Third ◽  
Γ Subunit ◽  
Subunit Stoichiometry ◽  
The Central Nervous System

GABAA receptors are members of the Cys-loop family of ligand-gated ion channels which mediate most inhibitory neurotransmission in the central nervous system. These receptors are pentameric assemblies of individual subunits, including α1-6, β1-3, γ1-3, δ, ε, π, θ and ρ1-3. The majority of receptors are comprised of α, β and γ or δ subunits. Depending on the subunit composition, the receptors are located in either the synapses or extrasynaptic regions. The most abundant receptors are α1βγ2 receptors, which are activated and modulated by a variety of pharmacologically and clinically unrelated agents such as benzodiazepines, barbiturates, anaesthetics and neurosteroids, all of which bind at distinct binding sites located within the receptor complex. However, compared to αβγ, the binary αβ receptors lack a benzodiazepine α-γ2 interface. In pentameric αβ receptors, the third subunit is replaced with either an α1 or a β3 subunit leading to two distinct receptors that differ in subunit stoichiometry, 2α:3β or 3α:2β. The consequence of this is that 3α:2β receptors contain an α-α interface whereas 2α:3β receptors contain a β-β interface. Apart from the replacement of γ by α1 or β3 in binary receptors, the incorporation of ε subunit into GABAA receptors might be more complicated. As the ε subunit is not only capable of substituting the γ subunit, but also replacing the α/β subunits, receptors with altered stoichiometry and different pharmacological properties are produced. The different subunit arrangement of the receptors potentially constructs novel binding sites which may become new targets of the current or new drugs.

scholarly journals New Method for Analysis of the Temporomandibular Joint Using Cone Beam Computed Tomography

Sensors ◽  
2021 ◽  
Vol 21 (9) ◽  
pp. 3070
Author(s):  
Sebastian Iwaszenko ◽  
Jakub Munk ◽  
Stefan Baron ◽  
Adam Smoliński
Keyword(s):  
Computed Tomography ◽  
Temporomandibular Joint ◽  
Cross Section ◽  
Cone Beam Computed Tomography ◽  
Cone Beam ◽  
Section Plane ◽  
New Approach ◽  
Volume Of Interest ◽  
Gap Width

Modern dentistry commonly uses a variety of imaging methods to support diagnosis and treatment. Among them, cone beam computed tomography (CBCT) is particularly useful in presenting head structures, such as the temporomandibular joint (TMJ). The determination of the morphology of the joint is an important part of the diagnosis as well as the monitoring of the treatment results. It can be accomplished by measurement of the TMJ gap width at three selected places, taken at a specific cross-section. This study presents a new approach to these measurements. First, the CBCT images are denoised using curvilinear methods, and the volume of interest is determined. Then, the orientation of the vertical cross-section plane is computed based on segmented axial sections of the TMJ head. Finally, the cross-section plane is used to determine the standardized locations, at which the width of the gap between condyle and fossa is measured. The elaborated method was tested on selected TMJ CBCT scans with satisfactory results. The proposed solution lays the basis for the development of an autonomous method of TMJ index identification.

Visualization of molecular binding sites at the nanoscale in the lift-up mode by amplitude-modulation atomic force microscopy

Nanoscale ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 4213-4220
Author(s):  
Tatsuhiro Maekawa ◽  
Takashi Nyu ◽  
Evan Angelo Quimada Mondarte ◽  
Hiroyuki Tahara ◽  
Kasinan Suthiwanich ◽  
...  
Keyword(s):  
Atomic Force Microscopy ◽  
Molecular Recognition ◽  
Amplitude Modulation ◽  
Binding Sites ◽  
Local Distribution ◽  
New Approach ◽  
Molecular Binding ◽  
Force Microscopy ◽  
Atomic Force ◽  
Recognition Sites

We report a new approach to visualize the local distribution of molecular recognition sites with nanoscale resolution by amplitude-modulation atomic force microscopy.

scholarly journals Synthesis of oxadiazole-2-oxide derivatives as potential drug candidates for schistosomiasis targeting SjTGR

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Gongming Li ◽  
Qingqing Guo ◽  
Chao Feng ◽  
Huan Chen ◽  
Wenjiao Zhao ◽  
...  
Keyword(s):  
Schistosoma Japonicum ◽  
Inhibitory Activity ◽  
Pyridine Ring ◽  
New Drugs ◽  
Wild Type ◽  
Drug Candidates ◽  
Structure Activity ◽  
Docking Method ◽  
Antigen Protein ◽  
Thioredoxin Glutathione Reductase

Abstract Background Schistosomiasis is a chronic parasitic disease that affects millions of people’s health worldwide. Because of the increasing drug resistance to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as potential anti-schistosomiasis reagents targeting thioredoxin glutathione reductase (TGR). Methods In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit a series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild-type Schistosoma japonicum TGR (wtSjTGR), in order to develop a new leading compound for schistosomiasis. Thirty-nine novel derivatives were prepared to test their activity toward both enzymes. The docking method was used to detect the binding site between the active molecule and SjTGR. The structure–activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed. Results It was found that several new derivatives, including compounds 6a–6d, 9ab, 9bd and 9be, demonstrated greater activity toward rSjTGR-Sec or SWAP containing wtSjTGR than did furoxan. Interestingly, all intermediates bearing hydroxy (6a–6d) showed excellent inhibitory activity against both enzymes. In particular, compound 6d with trifluoromethyl on a pyridine ring was found to have much higher inhibition toward both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan. Additionally, the docking method identified the possible matching sites between 6d and Schistosoma japonicum TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d. Conclusion The data obtained herein showed that 6d with trifluoromethyl on a pyridine ring could be a valuable leading compound for further study.

scholarly journals Molecular Recognition: Perspective and a New Approach

Sensors ◽  
2021 ◽  
Vol 21 (8) ◽  
pp. 2757
Author(s):  
W. Rudolf Seitz ◽  
Casey J. Grenier ◽  
John R. Csoros ◽  
Rongfang Yang ◽  
Tianyu Ren
Keyword(s):  
Molecular Recognition ◽  
Molecularly Imprinted Polymers ◽  
Binding Sites ◽  
Binding Kinetics ◽  
Molecularly Imprinted ◽  
New Approach ◽  
Imprinted Polymers ◽  
High Affinity ◽  
Water Blocking ◽  
High Level

This perspective presents an overview of approaches to the preparation of molecular recognition agents for chemical sensing. These approaches include chemical synthesis, using catalysts from biological systems, partitioning, aptamers, antibodies and molecularly imprinted polymers. The latter three approaches are general in that they can be applied with a large number of analytes, both proteins and smaller molecules like drugs and hormones. Aptamers and antibodies bind analytes rapidly while molecularly imprinted polymers bind much more slowly. Most molecularly imprinted polymers, formed by polymerizing in the presence of a template, contain a high level of covalent crosslinker that causes the polymer to form a separate phase. This results in a material that is rigid with low affinity for analyte and slow binding kinetics. Our approach to templating is to use predominantly or exclusively noncovalent crosslinks. This results in soluble templated polymers that bind analyte rapidly with high affinity. The biggest challenge of this approach is that the chains are tangled when the templated polymer is dissolved in water, blocking access to binding sites.

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