scholarly journals The Structural Determinants for α1-Adrenergic/Serotonin Receptors Activity among Phenylpiperazine-Hydantoin Derivatives

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 7025
Author(s):  
Katarzyna Kucwaj-Brysz ◽  
Anna Dela ◽  
Sabina Podlewska ◽  
Marek Bednarski ◽  
Agata Siwek ◽  
...  
Keyword(s):  
Radioligand Binding ◽  
Intrinsic Activity ◽  
Structural Determinants ◽  
Reciprocal Interactions ◽  
Pharmacodynamic Profile ◽  
Anxiolytic Agent ◽  
Hydantoin Derivatives ◽  
Sar Analysis ◽  
Significant Support ◽  
Insight Into

Several studies confirmed the reciprocal interactions between adrenergic and serotoninergic systems and the influence of these phenomena on the pathogenesis of anxiety. Hence, searching for chemical agents with a multifunctional pharmacodynamic profile may bring highly effective therapy for CNS disorders. This study presents a deep structural insight into the hydantoin-arylpiperazine group and their serotonin/α-adrenergic activity. The newly synthesized compounds were tested in the radioligand binding assay and the intrinsic activity was evaluated for the selected derivatives. The computer-aided SAR analysis enabled us to answer questions about the influence of particular structural fragments on selective vs. multifunctional activity. As a result of the performed investigations, there were two leading structures: (a) compound 12 with multifunctional adrenergic-serotonin activity, which is a promising candidate to be an effective anxiolytic agent; (b) compound 14 with high α1A/α1D affinity and selectivity towards α1B, which is recommended due to the elimination of probable cardiotoxic effect. The structural conclusions of this work provide significant support for future lead optimization in order to achieve the desired pharmacodynamic profile in searching for new CNS-modulating agents.

scholarly journals Identification of V6.51L as a selectivity hotspot in stereoselective A2B adenosine receptor antagonist recognition

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xuesong Wang ◽  
Willem Jespers ◽  
Rubén Prieto-Díaz ◽  
Maria Majellaro ◽  
Adriaan P. IJzerman ◽  
...  
Keyword(s):  
Radioligand Binding ◽  
Structural Data ◽  
Binding Mode ◽  
Selective Recognition ◽  
Chiral Hplc ◽  
Binding Assays ◽  
Structural Determinants ◽  
X Ray Crystallography ◽  
Adenosine Receptor Antagonist ◽  
Energy Perturbation

AbstractThe four adenosine receptors (ARs) A1AR, A2AAR, A2BAR, and A3AR are G protein-coupled receptors (GPCRs) for which an exceptional amount of experimental and structural data is available. Still, limited success has been achieved in getting new chemical modulators on the market. As such, there is a clear interest in the design of novel selective chemical entities for this family of receptors. In this work, we investigate the selective recognition of ISAM-140, a recently reported A2BAR reference antagonist. A combination of semipreparative chiral HPLC, circular dichroism and X-ray crystallography was used to separate and unequivocally assign the configuration of each enantiomer. Subsequently affinity evaluation for both A2A and A2B receptors demonstrate the stereospecific and selective recognition of (S)-ISAM140 to the A2BAR. The molecular modeling suggested that the structural determinants of this selectivity profile would be residue V2506.51 in A2BAR, which is a leucine in all other ARs including the closely related A2AAR. This was herein confirmed by radioligand binding assays and rigorous free energy perturbation (FEP) calculations performed on the L249V6.51 mutant A2AAR receptor. Taken together, this study provides further insights in the binding mode of these A2BAR antagonists, paving the way for future ligand optimization.

scholarly journals PURE POLITICKING! RACIALISED BLAME GAMES AND MORAL PANIC IN THE CASE OF A SOUTH AFRICAN HIGH SCHOOL

2020 ◽  
Vol 4 (1) ◽  
pp. 37-60
Author(s):  
MARTHINUS STANDER CONRADIE
Keyword(s):  
High School ◽  
South African ◽  
Moral Panic ◽  
Structural Determinants ◽  
African Education ◽  
South Africans ◽  
Black Politicians ◽  
South African Education ◽  
Practical Model ◽  
Insight Into

This study combines two discourse analytic frameworks, and explores the utility of this combination for unpacking journalistic opinions written in response to a polarising and racialised event in South African education: the Overvaal High School incident. It uncovers strategic constructions of racism within politicised blame games, in the context of Overvaal, and discloses how blame-assertion and blame-denial became implicated in framings of moral panic. Methodologically, this study relies on the concept race trouble, as well as a practical model of argumentation. In conjunction, these two approaches supply insight into both the calculated construction of racism, as well as the incorporation of these constructions into arguments aimed at rationalising blame-assertion and blame-denial. The results are interpreted within theorisations of moral panic. The findings showcase how arguments are produced to blame an individual politician for escalating racial antagonism around Overvaal, instead of offering a deeply historicised and contextualised account of the incident. Consequently, the arguments that shaped the opinion pieces, and the framing of racism involved in these arguments, ultimately obfuscate inquiry into structural determinants of racial inequity. Implicitly, this framing of racism and its incorporation into argumentation and blame games, produce a form of moral panic, in which South Africans racialised as white are construed as embattled by self-serving (black) politicians. Such politicians are vilified, or rendered as folk devils, and the results indicate how this process evades penetrating analyses of racialisation and its intersection with unequal education.  

scholarly journals A new chemoenzymatic semisynthetic approach provides novel insight into the role of phosphorylation beyond exon1 of Huntingtin and reveals N-terminal fragment length-dependent distinct mechanisms of aggregation

2021 ◽  
Author(s):  
Rajasekhar Kolla ◽  
Pushparathinam Gopinath ◽  
Jonathan Ricci ◽  
Andreas Reif ◽  
Iman Rostami ◽  
...  
Keyword(s):  
Disease Progression ◽  
Fragment Length ◽  
Neurodegenerative Disorder ◽  
Morphological Properties ◽  
Structural Determinants ◽  
Site Specific ◽  
Terminal Domain ◽  
Fibril Morphology ◽  
Insight Into

AbstractHuntington’s disease is a neurodegenerative disorder caused by the expansion of a polyglutamine (poly Q) repeat (>36Q) in the N-terminal domain of the huntingtin protein (Htt), which renders the protein or fragments thereof more prone to aggregate and form inclusions. Although several Htt N-terminal fragments of different lengths have been identified within Htt inclusions, most studies on the mechanisms, sequence, and structural determinants of Htt aggregation have focused on the Htt exon1 (Httex1). Herein, we investigated the aggregation properties of mutant N-terminal Htt fragments of various lengths (Htt171, Htt140, and Htt104) in comparison to mutant Httex1. We also present a new chemoenzymatic semisynthetic strategy that enables site-specific phosphorylation of Htt beyond Httex1. These advances yielded novel insights into how PTMs and structured domains beyond Httex1 influence aggregation mechanisms, kinetics, and fibril morphology of longer N-terminal Htt fragments. We demonstrate that phosphorylation at T107 significantly slowed its aggregation, whereases phosphorylation at T107 and S116 accelerated the aggregation of Htt171, underscoring the importance of crosstalk between different PTMs. We demonstrate that mutant Htt171 proteins aggregate via a different mechanism and form oligomers and fibrillar aggregates with morphological properties that are distinct from that of mutant Httex1. These observations suggest that different N-terminal fragments could have distinct mechanisms of aggregation and that a single polyQ-targeting anti-aggregation strategy may not effectively inhibit the aggregation of all N-terminal Htt fragments. Finally, our results underscore the importance of further studies to investigate the aggregation mechanisms of Htt fragments and how the various fragments interact with each other and influence Htt toxicity, pathology formation, and disease progression.Table of content

scholarly journals Structural insight into DNA binding and oligomerization of the multifunctional Cox protein of bacteriophage P2

2013 ◽  
Vol 42 (4) ◽  
pp. 2725-2735 ◽  
Author(s):  
Ronnie P.-A. Berntsson ◽  
Richard Odegrip ◽  
Wilhelmina Sehlén ◽  
Karin Skaar ◽  
Linda M. Svensson ◽  
...  
Keyword(s):  
Dna Binding ◽  
Protein Function ◽  
Specific Binding ◽  
Gene Products ◽  
Structural Determinants ◽  
Bacteriophage P2 ◽  
Defective Prophage ◽  
Key Residues ◽  
Functional Analyses ◽  
Insight Into

Abstract The Cox protein from bacteriophage P2 is a small multifunctional DNA-binding protein. It is involved in site-specific recombination leading to P2 prophage excision and functions as a transcriptional repressor of the P2 Pc promoter. Furthermore, it transcriptionally activates the unrelated, defective prophage P4 that depends on phage P2 late gene products for lytic growth. In this article, we have investigated the structural determinants to understand how P2 Cox performs these different functions. We have solved the structure of P2 Cox to 2.4 Å resolution. Interestingly, P2 Cox crystallized in a continuous oligomeric spiral with its DNA-binding helix and wing positioned outwards. The extended C-terminal part of P2 Cox is largely responsible for the oligomerization in the structure. The spacing between the repeating DNA-binding elements along the helical P2 Cox filament is consistent with DNA binding along the filament. Functional analyses of alanine mutants in P2 Cox argue for the importance of key residues for protein function. We here present the first structure from the Cox protein family and, together with previous biochemical observations, propose that P2 Cox achieves its various functions by specific binding of DNA while wrapping the DNA around its helical oligomer.

scholarly journals The X-Ray Structure of the Haloalcohol Dehalogenase HheA from Arthrobacter sp. Strain AD2: Insight into Enantioselectivity and Halide Binding in the Haloalcohol Dehalogenase Family

2006 ◽  
Vol 188 (11) ◽  
pp. 4051-4056 ◽  
Author(s):  
René M. de Jong ◽  
Kor H. Kalk ◽  
Lixia Tang ◽  
Dick B. Janssen ◽  
Bauke W. Dijkstra
Keyword(s):  
Tertiary Structure ◽  
Halogen Bond ◽  
Environmental Pollutants ◽  
Binding Pocket ◽  
Catalytic Triad ◽  
Side Chain ◽  
Structural Determinants ◽  
Substrate Binding Pocket ◽  
X Ray ◽  
Insight Into

ABSTRACT Haloalcohol dehalogenases are bacterial enzymes that cleave the carbon-halogen bond in short aliphatic vicinal haloalcohols, like 1-chloro-2,3-propanediol, some of which are recalcitrant environmental pollutants. They use a conserved Ser-Tyr-Arg catalytic triad to deprotonate the haloalcohol oxygen, which attacks the halogen-bearing carbon atom, producing an epoxide and a halide ion. Here, we present the X-ray structure of the haloalcohol dehalogenase HheAAD2 from Arthrobacter sp. strain AD2 at 2.0-Å resolution. Comparison with the previously reported structure of the 34% identical enantioselective haloalcohol dehalogenase HheC from Agrobacterium radiobacter AD1 shows that HheAAD2 has a similar quaternary and tertiary structure but a much more open substrate-binding pocket. Docking experiments reveal that HheAAD2 can bind both enantiomers of the haloalcohol substrate 1-p-nitrophenyl-2-chloroethanol in a productive way, which explains the low enantiopreference of HheAAD2. Other differences are found in the halide-binding site, where the side chain amino group of Asn182 is in a position to stabilize the halogen atom or halide ion in HheAAD2, in contrast to HheC, where a water molecule has taken over this role. These results broaden the insight into the structural determinants that govern reactivity and selectivity in the haloalcohol dehalogenase family.

scholarly journals Kinetic Analysis ofPseudomonas aeruginosaArginine Deiminase Mutants and Alternate Substrates Provides Insight into Structural Determinants of Function†

Biochemistry ◽  
2006 ◽  
Vol 45 (4) ◽  
pp. 1162-1172 ◽  
Author(s):  
Xuefeng Lu ◽  
Ling Li ◽  
Rui Wu ◽  
Xiaohua Feng ◽  
Zhimin Li ◽  
...  
Keyword(s):  
Kinetic Analysis ◽  
Structural Determinants ◽  
Insight Into

Development of Flashplate™ Technology to Measure [35S]GTPyS Binding to Chinese Hamster Ovary Cell Membranes Expressing the Cloned Human 5-HTIB Receptor

1998 ◽  
Vol 3 (2) ◽  
pp. 101-105 ◽  
Author(s):  
J. Watson ◽  
J. V. Selkirk ◽  
A. M. Brown
Keyword(s):  
G Protein ◽  
Chinese Hamster Ovary ◽  
Radioligand Binding ◽  
Partial Agonist ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Ovary Cell ◽  
Intrinsic Activity ◽  
Filtration Method ◽  
Gtpγs Binding

With the exponential rate at which proposed drugs are being produced for disease therapy, it is now essential to automate assays used to screen these compounds and increase throughput. This has been rapidly adopted for simple radioligand binding assays but is less amenable for certain functional screens. [35S]GTPγS binding represents a convenient method for screening ligands that bind to G protein-coupled receptors and, ultimately, stimulate G-protein activation. In this study we have investigated the use of 96-well FlashPlates™ (NEN DuPont, Stevenage, England) to measure [35S]GTPγS binding to human 5-HT1B receptors expressed in Chinese hamster ovary cells. The cells were added to the individual wells of the FlashPlate and incubated with [35S]GTPγS in the presence or absence of test drug and bound radioactivity measured in a 96-well spectrometer. 5-HT produced a stimulation of basal [35S]GTPγS binding, which was robust within and between experiments, with pEC50 = 8.1. The 5-HT1B partial agonist GR127935 (2′n-methyl-4′-5-methyl-1,2,4 oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide) caused a partial stimulation (pEC5o = 8.3, intrinsic activity = 0.7), and the selective 5-HTIB receptor antagonist SB-224289 (2,3,6,7-tetrahydro-1′-methyl-5-{2′-methyl-4′-[(5-methyl-1,2,4-oxadiazole-3-yl)biphenyl-4-yl]carbonyl}furo[2,3-flindole-3-spiro-4′-piperidine oxalate) displayed inverse agonism with pEC50 = 7.6. These results are similar to those obtained using the conventional filtration method and indicate that FlashPlate technology can provide a rapid method for measuring [35S]GTPγS binding.

scholarly journals An analysis of withdrawn shareholder proposals

2015 ◽  
Vol 15 (4) ◽  
pp. 546-562 ◽  
Author(s):  
Maggie Foley ◽  
Richard Cebula ◽  
Chulhee Jun ◽  
Robert Boylan
Keyword(s):  
Shareholder Value ◽  
Poor Performance ◽  
Content Type ◽  
Insider Ownership ◽  
Shareholder Proposals ◽  
Public Corporations ◽  
Practical Implications ◽  
Significant Support ◽  
Insight Into

Purpose – This study aims to analyze withdrawn shareholder proposals to gain insight into the role of shareholder proposals in the governance of public corporations. Design/methodology/approach – A cursory look at the data suggests that unions are the most likely group to withdraw proposals. The authors focus on the behavior of unions and find that unions often resubmit a shareholder proposal which had garnered significant support in the previous year, only to withdraw the proposal in the second year. Findings – The contention is that the proposals were withdrawn in Year 2 because the issue was settled in a manner agreeable to the union. Furthermore, this research suggests that unions are more likely to withdraw proposals when the prior years’ appeal is higher, when firms have a record of poor performance, lower insider ownership or relatively independent boards. This phenomenon suggests that unions submit and withdraw shareholder proposals strategically. The authors contend that unions use shareholder proposals and the withdrawal of proposals to improve conditions for union workers at the expense of shareholder value. Practical implications – This study suggests that unions submit and withdraw shareholder proposals strategically. The authors contend that unions use shareholder proposals and the withdrawal of proposals to improve conditions for union workers at the expense of shareholder value.

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