A unique gating mechanism revealed by the cryo-EM structure of monomeric ATP9A flippase.

Among mammalian P4-ATPase flippases, only ATP9A and ATP9B do not require the auxiliary subunit CDC50 protein. Whilst its yeast homologue, Neo1, is essential for cell survival, little is known about mammalian ATP9A. We present cryo-EM structures of human monomeric ATP9A at a resolution reaching to 2.

Computational and evaluation of sumac-derived Rutan compounds towards Sars-CoV-2 M inhibition.

The emergence of the SARS-CoV-2 virus caused the COVID-19 outbreak leading to a global pandemic. Natural substances started being screened for their antiviral activity by computational and techniques. Here, we evaluated the anti-SARS-CoV-2 main protease (M) efficacy of Rutan, which contains five polyphenols (R5, R6, R7, R7', and R8) extracted from sumac L.

Molecular Structure of the Na,K-ATPase α4β1 Isoform in Its Ouabain-Bound Conformation.

Na,K-ATPase is the active ion transport system that maintains the electrochemical gradients for Na and K across the plasma membrane of most animal cells. Na,K-ATPase is constituted by the association of two major subunits, a catalytic α and a glycosylated β subunit, both of which exist as different isoforms (in mammals known as α1, α2, α3, α4, β1, β2 and β3). Na,K-ATPase α and β isoforms assemble in different combinations to produce various isozymes with tissue specific expression and distinct biochemical properties.

Insights into Molecular Interactions and Biological Effect of Natural Stilbenoids at the TRPA1 Ion Channel.

Natural stilbenoids, polyphenolic compounds notably found in Scots pine and Norway spruce, have been shown to exhibit analgesic and anti-inflammatory effects through the TRPA1 channel, making them promising hits for the development of novel agents to treat inflammatory diseases and pain. In this study, we computationally investigated the putative binding sites of natural stilbenoids at the TRPA1 channel. Specifically, we employed molecular docking and MD simulation approaches to explore three known ligand binding sites at TRPA1.

Stilbenoid compounds inhibit NF-κB-mediated inflammatory responses in the intestine.

Introduction: Stilbenoid compounds have been described to have anti-inflammatory properties in animal models , and have been shown to inhibit Ca2+-influx through the transient receptor potential ankyrin 1 (TrpA1).

Methods: To study how stilbenoid compounds affect inflammatory signaling , we have utilized the fruit fly, , as a model system. To induce intestinal inflammation in the fly, we have fed flies with the intestinal irritant dextran sodium sulphate (DSS).

Deciphering the binding site and mechanism of new methylene blue with serum albumins: A multispectroscopic and computational investigation.

Herein, the interaction mechanism of new methylene blue (NMB) with human serum albumin (HSA) and bovine serum albumin (BSA) was carefully investigated both experimentally and conceptually, employing experimental and insilico analysis. The steady-state emission spectral studies showed that the emission intensity of HSA and BSA was quenched significantly by NMB. The findings of the Stern-Volmer and double logarithmic plot revealed that the observed emission quenching process was through a static quenching mechanism and the measured binding constant values (K) for HSA-NMB and BSA-NMB are 2.

Effect of Electric Field on α-Synuclein Fibrils: Revealed by Molecular Dynamics Simulations.

The self-association of amylogenic proteins to the fibril form is considered a pivotal factor in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). PD causes unintended or uncontrollable movements in its common symptoms. α-synuclein is the major cause of PD development and thus has been the main target of numerous studies to suppress and sequester its expression or effectively degrade it.

Bias-force guided simulations combined with experimental validations towards GPR17 modulators identification.

Glioblastoma Multiforme (GBM) is known to be by far the most aggressive brain tumor to affect adults. The median survival rate of GBM patient's is < 15 months, while the GBM cells aggressively develop resistance to chemo- and radiotherapy with their self-renewal capacity which suggests the pressing need to develop novel preventative measures. We have recently proved that GPR17 -an orphan G protein-coupled receptor- is highly expressed on the GBM cell surface and it has a vital role to play in the disease progression.

Allosteric regulation of DNA binding and target residence time drive the cytotoxicity of phthalazinone-based PARP-1 inhibitors.

Allosteric coupling between the DNA binding site to the NAD-binding pocket drives PARP-1 activation. This allosteric communication occurs in the reverse direction such that NAD mimetics can enhance PARP-1's affinity for DNA, referred to as type I inhibition. The cellular effects of type I inhibition are unknown, largely because of the lack of potent, membrane-permeable type I inhibitors.

Multispectroscopic and Computational Investigations on the Binding Mechanism of Dicaffeoylquinic Acids with Ovalbumin.

Recently, studies on the interactions between ovalbumin (OVA) and polyphenols have received a great deal of interest. This study explored the conformational changes and the interaction mechanism of the binding between OVA and chlorogenic acid (CGA) isomers such as 3,4-dicaffeoylquinic acids (3,4-diCQA), 4,5-dicaffeoylquinic acids (4,5-diCQA), and 3,5-dicaffeoylquinic acids (3,5-diCQA) using multispectroscopic and in silico analyses. The emission spectra show that the diCQAs caused strong quenching of OVA fluorescence under different temperatures through a static quenching mechanism with hydrogen bond (H-bond) and van der Waals (vdW) interactions.

Mechanistic Insights into SARS-CoV-2 Main Protease Inhibition Reveals Hotspot Residues.

The main protease (M) is a key enzyme responsible for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication that causes the spread of the global pandemic novel coronavirus (nCOVID-19) infection. In the present study, multiple computational approaches such as docking, long-range molecular dynamics (MD) simulations, and binding free-energy (BFE) estimation techniques were employed to investigate the mechanistic basis of the high-affinity inhibitors─GC-376, Calpain XII, and Calpain II (hereafter Calpain as Cal) from the literature─binding to M. Redocking GC-376 and docking Cal XII and Cal II inhibitors to M were able to reproduce all crucial interactions like the X-ray conformation.

Mapping the Molecular Architecture Required for Lipid-Binding Pockets Using a Subset of Established and Orphan G-Protein Coupled Receptors.

G-protein coupled receptors (GPCRs) sense a wide variety of stimuli, including lipids, and transduce signals to the intracellular environment to exert various physiological responses. However, the structural features of GPCRs responsible for detecting and triggering responses to distinct lipid ligands have only recently begun to be revealed. 14,15-epoxyeicosatrienoic acid (14,15-EET) is one such lipid mediator that plays an essential role in the vascular system, displaying both vasodilatory and anti-inflammatory properties.

Wnt/β-catenin Antagonists: Exploring New Avenues to Trigger Old Drugs in Alleviating Glioblastoma Multiforme.

Background: Glioblastoma Multiforme (GBM) is one of the most heterogeneous primary brain tumors with high mortality. In spite of the current therapeutic approaches, the survival rate remains poor, with death occurring within 12 to 15 months after the preliminary diagnosis. This warrants the need for an effective treatment modality.

Investigation into the site-specific binding interactions between chlorogenic acid and ovalbumin using multi-spectroscopic and in silico simulation studies.

The binding interactions of bioactive compounds with proteins are of great importance in the food, biochemistry and pharmaceutical fields. Herein, the binding mechanisms between 5-O-caffeoylquinic acid (5-CQA) and ovalbumin (OVA) were investigated by multi-spectroscopic studies combined with docking and molecular dynamics (MD) simulations. The emission intensity of OVA was quenched by 5-CQA and Stern-Volmer analysis indicated the existence of a static suppression by OVA-5-CQA complex formation.

Predicted Hotspot Residues Involved in Allosteric Signal Transmission in Pro-Apoptotic Peptide-Mcl1 Complexes.

Mcl1 is a primary member of the Bcl-2 family-anti-apoptotic proteins (AAP)-that is overexpressed in several cancer pathologies. The apoptotic regulation is mediated through the binding of pro-apoptotic peptides (PAPs) (e.g.

Disruption of conserved polar interactions causes a sequential release of Bim mutants from the canonical binding groove of Mcl1.

Mcl1 is an important anti-apoptotic member of the Bcl2 family proteins that are upregulated in several cancer malignancies. The canonical binding groove (CBG) located at the surface of Mcl1 exhibits a critical role in binding partners selectively via the BH3-domain of pro-apoptotic Bcl2 family members that trigger the downregulation of Mcl1 function. There are several crystal structures of point-mutated pro-apoptotic Bim peptides in complex with Mcl1.

Synthesis and Evaluation of Anisomelic acid-like Compounds for the Treatment of HPV-Mediated Carcinomas.

The vast majority of cervical and 75% of oropharyngeal carcinomas are triggered by infection with a type of high-risk oncogenic human papillomavirus (HPV). It is well-known that E6 and E7 oncoproteins are critical for viral-induced cancer, and hence, they represent valuable targets for therapeutic intervention in HPV-mediated cancers. Our earlier research on the cembranoid, anisomelic acid (AA) showed that, AA has the potential to induce apoptosis in HPV cells by the depletion of E6 and E7 oncoproteins.

Exploring the binding mechanism between methylene blue and ovalbumin using spectroscopic analyses and computational simulations.

The detailed investigation of methylene blue (MB) dye with ovalbumin (OVA) was examined by multispectroscopic and computational techniques. The experimental results of emission spectral studies displayed that the quenching behaviour of OVA with MB dye is due to static quenching mechanism. Isothermal titration calorimetry experimental results suggested that the binding of MB dye became favoured with the aid of a favourable entropy contribution and negative enthalpy.

Molecular interaction studies of some Co(III)-surfactants with the transport protein.

The present work describes the synthesis and the molecular interaction of two single-chain Co(III)-coordinated surfactant complexes with a plasma protein, human serum albumin by using various biophysical and in silico techniques. The experimental data reveals that like ordinary classical surfactants, our metallosurfactants also have the tendency to associate themselves and form micelles at critical micelle concentration. The thermodynamic parameters (ΔH°, ΔS°, and ΔG°) derived from the experiment demonstrates that the alkyl chain length and the head group of the Co(III)-surfactant complexes played a vital role in the binding process.

Unraveling the molecular mechanism of benzothiophene and benzofuran scaffold-merged compounds binding to anti-apoptotic Myeloid cell leukemia 1.

Myeloid cell leukemia 1 (Mcl1), is an antiapoptotic member of the Bcl-2 family proteins, has gained considerable importance due to its overexpression activity prevents the oncogenic cells to undergo apoptosis. This overexpression activity of Mcl1 eventually develops strong resistance to a wide variety of anticancer agents. Therefore, designing novel inhibitors with potentials to elicit higher binding affinity and specificity to inhibit Mcl1 activity is of greater importance.

Prediction of Hot Spots at Myeloid Cell Leukemia-1-Inhibitor Interface Using Energy Estimation and Alanine Scanning Mutagenesis.

Myeloid cell leukemia 1 (Mcl1) is an antiapoptotic protein that plays central role in apoptosis regulation. Also, Mcl1 has the potency to resist apoptotic cues resulting in up-regulation and cancer cell protection. A molecular probe that has the potential to specifically target Mcl1 and thereby provoke its down-regulatory activity is very essential.

In silico approaches to evaluate the molecular properties of organophosphate compounds to inhibit acetylcholinesterase activity in housefly.

Organophosphate compounds (OPC) have become the primary choice as insecticides and are widely used across the world. Additionally, OPCs were also commonly used as a chemical warfare agent that triggers a great challenge to public safety. Exposure of OPCs to human causes immediate excitation of cholinergic neurotransmission through transient elevation of synaptic acetylcholine (ACh) levels and accumulations.

Deciphering the crucial molecular properties of a series of Benzothiazole Hydrazone inhibitors that targets anti-apoptotic Bcl-xL protein.

The Bcl-2 family proteins are the central regulators of apoptosis. Due to its predominant role in cancer progression, the Bcl-2 family proteins act as attractive therapeutic targets. Recently, molecular series of Benzothiazole Hydrazone (BH) inhibitors that exhibits drug-likeness characteristics, which selectively targets Bcl-xL have been reported.

Deciphering the crucial residues involved in heterodimerization of Bak peptide and anti-apoptotic proteins for apoptosis.

B-cell lymphoma 2 (Bcl-2) family proteins are the central regulators of apoptosis, functioning via mitochondrial outer membrane permeabilization. The family members are involved in several stages of apoptosis regulation. The overexpression of the anti-apoptotic proteins leads to several cancer pathological conditions.

Plasma Protein Binding of Anisomelic Acid: Spectroscopy and Molecular Dynamic Simulations.

Anisomelic acid (AA) is a macrocyclic cembranolide compound extracted from Anisomeles herbal species. Recently, we have shown that AA possesses both anticancer and antiviral activity. However, to date, the plasma protein binding properties of AA are unknown.