scholarly journals Backbone Conformation Shifts in X-ray Structures of Human Acetylcholinesterase upon Covalent Organophosphate Inhibition

Crystals ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1270
Author(s):  
Stephanie Luedtke ◽  
Celine Bojo ◽  
Yunshen Li ◽  
Emilio Luna ◽  
Bianca Pomar ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Nerve Agents ◽  
Ethoxy Group ◽  
X Ray ◽  
Backbone Conformation ◽  
Op Nerve Agents ◽  
Definition Of ◽  
Alpha Carbon

Conformations of Cα backbones in X-ray structures of most organophosphate (OP)-inhibited human acetylcholinesterases (hAChEs) have been previously shown to be similar to that of the native hAChE. One of the exceptions is the structure of the diethylphosphoryl-hAChE conjugate, where stabilization of a large ethoxy group into the acyl pocket (AP) of hAChE-triggered notable loop distortions and consequential dissociation of the hAChE homodimer. Recently, six X-ray structures of hAChE conjugated with large OP nerve agents of the A-type, Novichoks, have been deposited to PDB. In this study we analyzed backbone conformation shifts in those structures, as well as in OP-hAChE conjugates formed by Paraoxon, Soman, Tabun, and VX. A Java-based pairwise alpha carbon comparison tool (PACCT 3) was used for analysis. Surprisingly, despite the snug fit of large substituents on phosphorus, inside Novichok-conjugated hAChEs only minor conformational changes were detected in their backbones. Small magnitudes of observed changes were due to a 1.2–2.4 Å shift of the entire conjugated OP away from the AP. It thus appears that the small AP of AChEs can accommodate, without distortion, substituents of the size of ethoxy or butyryl groups, provided that conjugated OP is “pulled” away from the AP. This observation has practical consequences in the structure-based design of nucleophilic reactivation antidotes as well as in the definition of the AChE specificity that relies on the size of its AP.

scholarly journals Overlay-independent comparisons of X-ray structures reveal small, systematic conformational changes in liganded acetylcholinesterase

2017 ◽  
Vol 118 (4) ◽  
Author(s):  
Jacqueline Rohrer ◽  
Morgana Sidhom ◽  
Jingting Han ◽  
Zoran Radić
Keyword(s):  
Conformational Changes ◽  
Site Directed Mutagenesis ◽  
Reversible Inhibitor ◽  
Tertiary Structures ◽  
X Ray ◽  
3D Structures ◽  
Comparison Approach ◽  
Quaternary Structures ◽  
Alpha Carbon ◽  
Covalent Conjugates

Background and Purpose: Comparisons of macromolecular 3D structures by minimizing corresponding atom RMSDs can by virtue of averaging, hide small unexpected deviations caused by ligand binding or site-directed mutagenesis. We developed an overlay-independent comparison approach and used it to compare selected, PDB structures of acetylcholinesterase (AChE; EC 3.1.1.7) in the apo state, in complexes with reversible ligands, in covalent conjugates or upon AChE mutagenesis. Methods: The active serine alpha carbon of the AChE monomer was used as a frame of reference for each of the structures, and distances calculated to remaining alpha carbons of the monomer backbone. Differences in distances at corresponding backbone positions from pairwise comparisons with apo-AChE structures were taken as a measure of changes in tertiary structures of liganded or mutant AChE monomers.Results: This analysis revealed small, yet significant backbone shifts in monomeric tertiary structures of AChEs. While reversible complexes with neurotoxin Fas2 showed global expansion of AChE monomer backbones, covalent conjugates at the active serine and high affinity reversible inhibitor hupA complexes revealed backbone compression towards the active serine. In some of AChE homodimers 0.6 - 1Å shifts of monomer backbone affected crystallographic quaternary structures by causing significant, up to seven degree tilts in monomers, relative to angles measured in the apo-AChE.Conclusions: Small but systematic differences detected in tertiary structures of liganded or mutagenized AChEs appear consistent with larger magnitude alterations of several AChE homodimer quaternary structures. Those observations vaildate our overlay-independent approach for detecting small, yet significant, tertiary backbone shifts in macromolecular 3D structures.

scholarly journals Shifts in Backbone Conformation of Acetylcholinesterases upon Binding of Covalent Inhibitors, Reversible Ligands and Substrates

Crystals ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1557
Author(s):  
Zoran Radić
Keyword(s):  
Conformational Changes ◽  
Dynamic Properties ◽  
Catalytic Reactions ◽  
Structural Element ◽  
X Ray ◽  
Ache Inhibitors ◽  
Allosteric Interaction ◽  
Backbone Conformation ◽  
Covalent Inhibitors ◽  
Planar Geometries

The influence of ligand binding to human, mouse and Torpedo californica acetylcholinesterase (EC 3.1.1.7; AChE) backbone structures is analyzed in a pairwise fashion by comparison with X-ray structures of unliganded AChEs. Both complexes with reversible ligands (substrates and inhibitors) as well as covalently interacting ligands leading to the formation of covalent AChE conjugates of tetrahedral and of trigonal-planar geometries are considered. The acyl pocket loop (AP loop) in the AChE backbone is recognized as the conformationally most adaptive, but not necessarily sterically exclusive, structural element. Conformational changes of the centrally located AP loop coincide with shifts in C-terminal α-helical positions, revealing interacting components for a potential allosteric interaction within the AChE backbone. The stabilizing power of the aromatic choline binding site, with the potential to attract and pull fitting entities covalently tethered to the active Ser, is recognized. Consequently, the pull can promote catalytic reactions or relieve steric pressure within the impacted space of the AChE active center gorge. These dynamic properties of the AChE backbone inferred from the analysis of static X-ray structures contribute towards a better understanding of the molecular template important in the structure-based design of therapeutically active molecules, including AChE inhibitors as well as reactivators of conjugated, inactive AChE.

scholarly journals Characterization of Spent Ni-MH Batteries

2012 ◽  
Vol 730-732 ◽  
pp. 569-574
Author(s):  
Marta Cabral ◽  
Fernanda Margarido ◽  
Carlos A. Nogueira
Keyword(s):  
Quantitative Analysis ◽  
Electrode Materials ◽  
Phase Identification ◽  
Recycling Process ◽  
X Ray ◽  
Leaching Experiments ◽  
Plastic Components ◽  
Definition Of ◽  
Physical And Chemical

Spent Ni-MH batteries are not considered too dangerous for the environment, but they have a considerable economical value due to the chemical composition of electrodes which are highly concentrated in metals. The present work aimed at the physical and chemical characterisation of spent cylindrical and thin prismatic Ni-MH batteries, contributing for a better definition of the recycling process of these spent products. The electrode materials correspond to more than 50% of the batteries weight and contain essentially nickel and rare earths (RE), and other secondary elements (Co, Mn, Al). The remaining components are the steel parts from the external case and supporting grids (near 30%) containing Fe and Ni, and the plastic components (<10%). Elemental quantitative analysis showed that the electrodes are highly concentrated in metals. Phase identification by X-ray powder diffraction combined with chemical analysis and leaching experiments allowed advancing the electrode materials composition. The cathode is essentially constituted by 6% metallic Ni, 66% Ni(OH)2, 4.3% Co(OH)2 and the anode consists mainly in 62% RENi5 and 17% of substitutes and/or additives such as Co, Mn and Al.

scholarly journals Reliable Learning with PDE-Based CNNs and DenseNets for Detecting COVID-19, Pneumonia, and Tuberculosis from Chest X-Ray Images

Mathematics ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 434
Author(s):  
Anca Nicoleta Marginean ◽  
Delia Doris Muntean ◽  
George Adrian Muntean ◽  
Adelina Priscu ◽  
Adrian Groza ◽  
...  
Keyword(s):  
Transfer Learning ◽  
Negative Impact ◽  
X Ray ◽  
Domain Specific ◽  
Direct Training ◽  
Public Data ◽  
Normal Chest ◽  
Chest X Ray ◽  
The Stability ◽  
Definition Of

It has recently been shown that the interpretation by partial differential equations (PDEs) of a class of convolutional neural networks (CNNs) supports definition of architectures such as parabolic and hyperbolic networks. These networks have provable properties regarding the stability against the perturbations of the input features. Aiming for robustness, we tackle the problem of detecting changes in chest X-ray images that may be suggestive of COVID-19 with parabolic and hyperbolic CNNs and with domain-specific transfer learning. To this end, we compile public data on patients diagnosed with COVID-19, pneumonia, and tuberculosis, along with normal chest X-ray images. The negative impact of the small number of COVID-19 images is reduced by applying transfer learning in several ways. For the parabolic and hyperbolic networks, we pretrain the networks on normal and pneumonia images and further use the obtained weights as the initializers for the networks to discriminate between COVID-19, pneumonia, tuberculosis, and normal aspects. For DenseNets, we apply transfer learning twice. First, the ImageNet pretrained weights are used to train on the CheXpert dataset, which includes 14 common radiological observations (e.g., lung opacity, cardiomegaly, fracture, support devices). Then, the weights are used to initialize the network which detects COVID-19 and the three other classes. The resulting networks are compared in terms of how well they adapt to the small number of COVID-19 images. According to our quantitative and qualitative analysis, the resulting networks are more reliable compared to those obtained by direct training on the targeted dataset.

scholarly journals Unusual Conformational Changes in 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase as Revealed by X-ray Crystallography and NMR

2001 ◽  
Vol 276 (43) ◽  
pp. 40274-40281 ◽  
Author(s):  
Bing Xiao ◽  
Genbin Shi ◽  
Jinhai Gao ◽  
Jaroslaw Blaszczyk ◽  
Qin Liu ◽  
...  
Keyword(s):  
Conformational Changes ◽  
X Ray ◽  
X Ray Crystallography

X-ray photoemission studies of the interaction of metals and metal ions with DNA

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Esha Mishra ◽  
Subrata Majumder ◽  
Shikha Varma ◽  
Peter A. Dowben
Keyword(s):  
Heavy Metal ◽  
Metal Ions ◽  
Conformational Changes ◽  
Photoelectron Spectroscopy ◽  
X Ray ◽  
Surface Sensitivity ◽  
Metal Interaction ◽  
The Status ◽  
Sensitivity And Selectivity ◽  
Insight Into

Abstract X-ray Photoelectron Spectroscopy (XPS) has been used to study the interactions of heavy metal ions with DNA with some success. Surface sensitivity and selectivity of XPS are advantageous for identifying and characterizing the chemical and elemental structure of the DNA to metal interaction. This review summarizes the status of what amounts to a large part of the photoemission investigations of biomolecule interactions with metals and offers insight into the mechanism for heavy metal-bio interface interactions. Specifically, it is seen that metal interaction with DNA results in conformational changes in the DNA structure.

Factors affecting the amplitude of the τ angle in proteins: a revisitation

2017 ◽  
Vol 73 (7) ◽  
pp. 618-625 ◽  
Author(s):  
Nicole Balasco ◽  
Luciana Esposito ◽  
Luigi Vitagliano
Keyword(s):  
Protein Structures ◽  
Factors Affecting ◽  
X Ray ◽  
Backbone Conformation ◽  
Potential Factors ◽  
The Stability ◽  
Major Factors ◽  
The Impact ◽  
Open Issues

The protein folded state is the result of the fine balance of a variety of different forces. Even minor structural perturbations may have a significant impact on the stability of these macromolecules. Studies carried out in recent decades have led to the convergent view that proteins are endowed with a flexible spine. One of the open issues related to protein local backbone geometry is the identification of the factors that influence the amplitude of the τ (N—Cα—C) angle. Here, statistical analyses performed on an updated ensemble of X-ray protein structures by dissecting the contribution of the major factors that can potentially influence the local backbone geometry of proteins are reported. The data clearly indicate that the local backbone conformation has a prominent impact on the modulation of the τ angle. Therefore, a proper assessment of the impact of the other potential factors can only be appropriately evaluated when small (φ, ψ) regions are considered. Here, it is shown that when the contribution of the backbone conformation is removed by considering small (φ, ψ) areas, an impact of secondary structure, as defined byDSSP, and/or the residue type on τ is still detectable, although to a limited extent. Indeed, distinct τ-value distributions are detected for Pro/Gly and β-branched (Ile/Val) residues. The key role of the local backbone conformation highlighted here supports the use of variable local backbone geometry in protein refinement protocols.

The kinetics of conformational changes of α2 -macroglobulin determined by time resolved X-ray solution scattering

FEBS Letters ◽  
1994 ◽  
Vol 337 (2) ◽  
pp. 171-174 ◽  
Author(s):  
Hideo Arakawa ◽  
Takuji Urisaka ◽  
Hirotsugu Tsuruta ◽  
Yoshiyuki Amemiya ◽  
Hiroshi Kihara ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Time Resolved ◽  
X Ray ◽  
Α2 Macroglobulin ◽  
Kinetics Of
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