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 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.

Investigating the dynamic nature of the ABC transporters: ABCB1 and MsbA as examples for the potential synergies of MD theory and EPR applications

2015 ◽  
Vol 43 (5) ◽  
pp. 1023-1032 ◽  
Author(s):  
Thomas Stockner ◽  
Anna Mullen ◽  
Fraser MacMillan
Keyword(s):  
Crystal Structures ◽  
Conformational Changes ◽  
Abc Transporters ◽  
Epr Spectroscopy ◽  
Structural Information ◽  
Dynamic Properties ◽  
Molecular System ◽  
Synergistic Effects ◽  
Md Simulations ◽  
Substrate Spectrum

ABC transporters are primary active transporters found in all kingdoms of life. Human multidrug resistance transporter ABCB1, or P-glycoprotein, has an extremely broad substrate spectrum and confers resistance against chemotherapy drug treatment in cancer cells. The bacterial ABC transporter MsbA is a lipid A flippase and a homolog to the human ABCB1 transporter, with which it partially shares its substrate spectrum. Crystal structures of MsbA and ABCB1 have been solved in multiple conformations, providing a glimpse into the possible conformational changes the transporter could be going through during the transport cycle. Crystal structures are inherently static, while a dynamic picture of the transporter in motion is needed for a complete understanding of transporter function. Molecular dynamics (MD) simulations and electron paramagnetic resonance (EPR) spectroscopy can provide structural information on ABC transporters, but the strength of these two methods lies in the potential to characterise the dynamic regime of these transporters. Information from the two methods is quite complementary. MD simulations provide an all atom dynamic picture of the time evolution of the molecular system, though with a narrow time window. EPR spectroscopy can probe structural, environmental and dynamic properties of the transporter in several time regimes, but only through the attachment sites of an exogenous spin label. In this review the synergistic effects that can be achieved by combining the two methods are highlighted, and a brief methodological background is also presented.

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

scholarly journals Predicting data quality in biological X-ray solution scattering

2018 ◽  
Vol 74 (8) ◽  
pp. 727-738
Author(s):  
Chenzheng Wang ◽  
Yuexia Lin ◽  
Devin Bougie ◽  
Richard E. Gillilan
Keyword(s):  
Conformational Changes ◽  
Sample Path ◽  
Flow Time ◽  
Photon Flux ◽  
Detector Efficiency ◽  
Time Resolved ◽  
Short Sample ◽  
X Ray ◽  
Path Lengths ◽  
Flux Energy

Biological small-angle X-ray solution scattering (BioSAXS) is now widely used to gain information on biomolecules in the solution state. Often, however, it is not obvious in advance whether a particular sample will scatter strongly enough to give useful data to draw conclusions under practically achievable solution conditions. Conformational changes that appear to be large may not always produce scattering curves that are distinguishable from each other at realistic concentrations and exposure times. Emerging technologies such as time-resolved SAXS (TR-SAXS) pose additional challenges owing to small beams and short sample path lengths. Beamline optics vary in brilliance and degree of background scatter, and major upgrades and improvements to sources promise to expand the reach of these methods. Computations are developed to estimate BioSAXS sample intensity at a more detailed level than previous approaches, taking into account flux, energy, sample thickness, window material, instrumental background, detector efficiency, solution conditions and other parameters. The results are validated with calibrated experiments using standard proteins on four different beamlines with various fluxes, energies and configurations. The ability of BioSAXS to statistically distinguish a variety of conformational movements under continuous-flow time-resolved conditions is then computed on a set of matched structure pairs drawn from the Database of Macromolecular Motions (http://molmovdb.org). The feasibility of experiments is ranked according to sample consumption, a quantity that varies by over two orders of magnitude for the set of structures. In addition to photon flux, the calculations suggest that window scattering and choice of wavelength are also important factors given the short sample path lengths common in such setups.

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