scholarly journals Transmembrane Peptides as a New Strategy to Inhibit Neuraminidase-1 Activation

2020 ◽  
Vol 8 ◽  
Author(s):  
Camille Albrecht ◽  
Andrey S. Kuznetsov ◽  
Aline Appert-Collin ◽  
Zineb Dhaideh ◽  
Maïté Callewaert ◽  
...  
Keyword(s):  
Biological Functions ◽  
Selective Inhibitors ◽  
Nmr Studies ◽  
Transmembrane Peptides ◽  
Sialidase Activity ◽  
New Strategy ◽  
Dimerization Interface ◽  
Human Disorders ◽  
Dynamics Simulations ◽  
Neu1 Sialidase

Sialidases, or neuraminidases, are involved in several human disorders such as neurodegenerative, infectious and cardiovascular diseases, and cancers. Accumulative data have shown that inhibition of neuraminidases, such as NEU1 sialidase, may be a promising pharmacological target, and selective inhibitors of NEU1 are therefore needed to better understand the biological functions of this sialidase. In the present study, we designed interfering peptides (IntPep) that target a transmembrane dimerization interface previously identified in human NEU1 that controls its membrane dimerization and sialidase activity. Two complementary strategies were used to deliver the IntPep into cells, either flanked to a TAT sequence or non-tagged for solubilization in detergent micelles. Combined with molecular dynamics simulations and heteronuclear nuclear magnetic resonance (NMR) studies in membrane-mimicking environments, our results show that these IntPep are able to interact with the dimerization interface of human NEU1, to disrupt membrane NEU1 dimerization and to strongly decrease its sialidase activity at the plasma membrane. In conclusion, we report here new selective inhibitors of human NEU1 of strong interest to elucidate the biological functions of this sialidase.

scholarly journals Detection of Neu1 Sialidase Activity in Regulating TOLL-like Receptor Activation

10.3791/2142 ◽  
2010 ◽  
Author(s):  
Schammim R. Amith ◽  
Preethi Jayanth ◽  
Trisha Finlay ◽  
Susan Franchuk ◽  
Alanna Gilmour ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Toll Like Receptor ◽  
Sialidase Activity ◽  
Neu1 Sialidase

scholarly journals The Droserasin 1 PSI: A Membrane-Interacting Antimicrobial Peptide from the Carnivorous Plant Drosera capensis

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1069
Author(s):  
Marc A. Sprague-Piercy ◽  
Jan C. Bierma ◽  
Marquise G. Crosby ◽  
Brooke P. Carpenter ◽  
Gemma R. Takahashi ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Disulfide Bonds ◽  
Lipid Vesicles ◽  
Carnivorous Plant ◽  
Nmr Studies ◽  
Biophysical Characterization ◽  
Head Groups ◽  
Wide Range ◽  
Dynamics Simulations ◽  
Lipid Nanodiscs

The Droserasins, aspartic proteases from the carnivorous plant Drosera capensis, contain a 100-residue plant-specific insert (PSI) that is post-translationally cleaved and independently acts as an antimicrobial peptide. PSIs are of interest not only for their inhibition of microbial growth, but also because they modify the size of lipid vesicles and strongly interact with biological membranes. PSIs may therefore be useful for modulating lipid systems in NMR studies of membrane proteins. Here we present the expression and biophysical characterization of the Droserasin 1 PSI (D1 PSI.) This peptide is monomeric in solution and maintains its primarily α -helical secondary structure over a wide range of temperatures and pH values, even under conditions where its three disulfide bonds are reduced. Vesicle fusion assays indicate that the D1 PSI strongly interacts with bacterial and fungal lipids at pH 5 and lower, consistent with the physiological pH of D. capensis mucilage. It binds lipids with a variety of head groups, highlighting its versatility as a potential stabilizer for lipid nanodiscs. Solid-state NMR spectra collected at a field strength of 36 T, using a unique series-connected hybrid magnet, indicate that the peptide is folded and strongly bound to the membrane. Molecular dynamics simulations indicate that the peptide is stable as either a monomer or a dimer in a lipid bilayer. Both the monomer and the dimer allow the passage of water through the membrane, albeit at different rates.

scholarly journals A Computational Probe into the Structure and Dynamics of the Full-Length Toll-Like Receptor 3 in a Phospholipid Bilayer

2020 ◽  
Vol 21 (8) ◽  
pp. 2857
Author(s):  
Mahesh Chandra Patra ◽  
Maria Batool ◽  
Muhammad Haseeb ◽  
Sangdun Choi
Keyword(s):  
Interleukin 1 ◽  
Full Length ◽  
Phospholipid Bilayer ◽  
Type I Interferons ◽  
Type I ◽  
Toll Like Receptor ◽  
Phosphate Backbone ◽  
Dimerization Interface ◽  
Dynamics Simulations ◽  
Tir Domains

Toll-like receptor 3 (TLR3) provides the host with antiviral defense by initiating an immune signaling cascade for the production of type I interferons. The X-ray structures of isolated TLR3 ectodomain (ECD) and transmembrane (TM) domains have been reported; however, the structure of a membrane-solvated, full-length receptor remains elusive. We investigated an all-residue TLR3 model embedded inside a phospholipid bilayer using molecular dynamics simulations. The TLR3-ECD exhibited a ~30°–35° tilt on the membrane due to the electrostatic interaction between the N-terminal subdomain and phospholipid headgroups. Although the movement of dsRNA did not affect the dimer integrity of TLR3, its sugar-phosphate backbone was slightly distorted with the orientation of the ECD. TM helices exhibited a noticeable tilt and curvature but maintained a consistent crossing angle, avoiding the hydrophobic mismatch with the bilayer. Residues from the αD helix and the CD and DE loops of the Toll/interleukin-1 receptor (TIR) domains were partially absorbed into the lower leaflet of the bilayer. We found that the previously unknown TLR3-TIR dimerization interface could be stabilized by the reciprocal contact between αC and αD helices of one subunit and the αC helix and the BB loop of the other. Overall, the present study can be helpful to understand the signaling-competent form of TLR3 in physiological environments.

Prediction of the Tertiary Structure and the Dimerization Interface of FNR Protein in Klebsiella pneumoniae

2014 ◽  
Vol 936 ◽  
pp. 795-800
Author(s):  
Qing Rui Zhang ◽  
Xia Li
Keyword(s):  
Klebsiella Pneumoniae ◽  
Binding Sites ◽  
Tertiary Structure ◽  
Homology Modelling ◽  
Support Vector ◽  
Vector Machines ◽  
Fnr Protein ◽  
Dimerization Interface ◽  
Dynamics Simulations ◽  
Aerobic And Anaerobic

FNR (fumarate nitrate reduction regulator) is an important oxygen regulation protein, which plays a major role in altering gene expression between aerobic and anaerobic conditions. In this study, the tertiary structure of FNR protein in Klebsiella pneumoniae was established using homology modelling. The model was modified and optimized using molecular mechanics and molecular dynamics simulations. In addition, Support Vector Machines (SVMs) was applied to predict the possible binding sites patches of FNR. The residues conservations were further analyzed and it was found that the Asn138-Ser162 region of FNR protein was the putative dimerization interface.

scholarly journals Divergence in dimerization and activity of primate APOBEC3C

2021 ◽  
Author(s):  
Amit Gaba ◽  
Mark A Hix ◽  
Sana Suhail ◽  
Ben Flath ◽  
Brock Boysan ◽  
...  
Keyword(s):  
Amino Acid ◽  
Antiviral Activity ◽  
World Monkey ◽  
Restriction Factors ◽  
Cytidine Deaminases ◽  
Host Restriction ◽  
Dimerization Interface ◽  
Dynamics Simulations ◽  
Vif Protein ◽  
Hiv 1

The APOBEC3 (A3) family of single-stranded DNA cytidine deaminases are host restriction factors that inhibit lentiviruses, such as HIV-1, in the absence of the Vif protein that causes their degradation. Deamination of cytidine in HIV-1 (-)DNA forms uracil that causes inactivating mutations when uracil is used as a template for (+)DNA synthesis. For APOBEC3C (A3C), the chimpanzee and gorilla orthologues are more active than human A3C, and the Old World Monkey A3C from rhesus macaque (rh) is not active against HIV-1. Multiple integrated analyses determined why rhA3C was not active against HIV-1 and how to increase this activity. Biochemical, virological, and coevolutionary analyses combined with molecular dynamics simulations showed that the key amino acids needed to promote rhA3C antiviral activity also promoted dimerization. Although rhA3C shares a similar dimer interface with hominid A3C, the key amino acid contacts were different. Overall, our results determine the basis for why rhA3C is less active than human A3C, establish the amino acid network for dimerization and increased activity, and track the loss and gain of A3C antiviral activity in primates. The coevolutionary analysis of the A3C dimerization interface provides a basis from which to analyze dimerization interfaces of other A3 family members.

scholarly journals MORC protein family-related signature within human disease and cancer

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Huan Wang ◽  
Ling Zhang ◽  
Qiuhua Luo ◽  
Jia Liu ◽  
Guiling Wang
Keyword(s):  
Cancer Progression ◽  
Coiled Coil ◽  
Diagnostic Tools ◽  
Disease Genes ◽  
Biological Functions ◽  
New Paradigm ◽  
Aberrant Expression ◽  
Domain Structures ◽  
Human Disorders ◽  
Epigenetic Regulators

AbstractThe microrchidia (MORC) family of proteins is a highly conserved nuclear protein superfamily, whose members contain common domain structures (GHKL-ATPase, CW-type zinc finger and coiled-coil domain) yet exhibit diverse biological functions. Despite the advancing research in previous decades, much of which focuses on their role as epigenetic regulators and in chromatin remodeling, relatively little is known about the role of MORCs in tumorigenesis and pathogenesis. MORCs were first identified as epigenetic regulators and chromatin remodelers in germ cell development. Currently, MORCs are regarded as disease genes that are involved in various human disorders and oncogenes in cancer progression and are expected to be the important biomarkers for diagnosis and treatment. A new paradigm of expanded MORC family function has raised questions regarding the regulation of MORCs and their biological role at the subcellular level. Here, we systematically review the progress of researching MORC members with respect to their domain architectures, diverse biological functions, and distribution characteristics and discuss the emerging roles of the aberrant expression or mutation of MORC family members in human disorders and cancer development. Furthermore, the illustration of related mechanisms of the MORC family has made MORCs promising targets for developing diagnostic tools and therapeutic treatments for human diseases, including cancers.

scholarly journals Interfacial Water Many-body Effects Drive Structural Dynamics and Allosteric interactions in SARS-CoV-2 Main Protease Dimerization Interface

2021 ◽  
Author(s):  
Dina El Ahdab ◽  
Louis Lagardère ◽  
Theo Jaffrelot Inizan ◽  
Frédéric Célerse ◽  
Chengwen Liu ◽  
...  
Keyword(s):  
Structural Dynamics ◽  
Adaptive Sampling ◽  
Many Body ◽  
Allosteric Site ◽  
Allosteric Interactions ◽  
Main Protease ◽  
Dimerization Interface ◽  
Bond Network ◽  
Dynamics Simulations ◽  
Many Body Interactions

Following our previous work (Chem. Sci., 2021, 12, 4889 – 4907), we study the structural dynamics of the SARS-CoV-2 Main Protease dimerization interface (apo dimer) by means of microsecond adaptive sampling molecular dynamics simulations (50 microseconds) using the AMOEBA polarizable force field (PFF). This interface is structured by a complex H-bond network that is only stable at physiological pH. Structural correlations analysis between its residues and the catalytic site confirms the presence of a buried allosteric site. However, noticeable differences in allosteric connectivity are observed between PFFs and non-PFFs. Interfacial polarizable water molecules are shown to appear at the heart of this discrepancy, since they are connected to the global interface H-bond network and able to adapt their dipole moment (and dynamics) to their diverse local physico-chemical micro-environments. The water-interface many-body interactions appear to drive the interface volume fluctuations and to therefore mediate the allosteric interactions with the catalytic cavity.

scholarly journals In Silico Exploration of Repurposing and Optimizing Traditional Chinese Medicine Rutin for Possibly Inhibiting SARS-CoV-2's Main Protease

2020 ◽  
Author(s):  
Tien Huynh ◽  
Haoran Wang ◽  
Wendy Cornell ◽  
Binquan Luan
Keyword(s):  
In Silico ◽  
Molecular Mechanisms ◽  
Herbal Medicines ◽  
Viral Proteins ◽  
Biological Functions ◽  
Rna Dependent Rna Polymerase ◽  
Global Pandemic ◽  
Main Protease ◽  
Dynamics Simulations ◽  
Viral Target

<div>Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic with very limited specific treatments. To fight COVID-19, various traditional antiviral medicines haveb been prescribed in China to infected patients with mild to moderate symptoms and received unexpected success in controlling the disease. However, the molecular mechanisms of how these herbal medicines interact with the virus have remained elusive. It is well known that the main protease (Mpro) of SARS-CoV-2 plays an important role in maturation of many viral proteins such as the RNA-dependent RNA polymerase. Here,we explore the underlying molecular mechanisms of the computationally determined top candidate–rutin, a key component in many traditional antiviral medicines such as Lianhuaqinwen and Shuanghuanlian, for inhibiting the viral target–Mpro. Using in silico methods (docking and molecular dynamics simulations), we revealed the dynamics and energetics of rutin when interacting with the Mpro of SARS-CoV-2, suggesting that the highly hydrophilic rutin molecule can be bound inside the Mpro’ pocket (active site) and possibly inhibit its biological functions. In addition, we optimized the structure of rutin and designed a more hydrophobic analog which satisfies the rule of five for western medicines and demonstrated that it possesses a much stronger binding affinity to the SARS-COV-2’s Mpro.<br></div>

scholarly journals Roughness of a transmembrane peptide reduces lipid membrane dynamics

2016 ◽  
Author(s):  
Marie Olšinová ◽  
Piotr Jurkiewicz ◽  
Jan Sýkora ◽  
Ján Sabó ◽  
Martin Hof ◽  
...  
Keyword(s):  
Rough Surface ◽  
Lipid Membrane ◽  
Cholesterol Content ◽  
Membrane Dynamics ◽  
Membrane Properties ◽  
Helical Structures ◽  
Transmembrane Peptides ◽  
Acyl Chains ◽  
Dynamics Simulations ◽  
And Function

Transmembrane domains integrate proteins into cellular membranes and support their function. The capacity of these prevalently a-helical structures in mammals to influence membrane properties is poorly understood. Combining experiments with molecular dynamics simulations, we provide evidence that helical transmembrane peptides with their rough surface reduce lateral mobility of membrane constituents. The molecular mechanism involves trapping of lipid acyl chains on the rough surface and segregation of cholesterol from the vicinity of peptides. The observations are supported by our toy model indicating strong effect of rough objects on membrane dynamics. Herein described effect has implications for the organization and function of biological membranes, especially the plasma membrane with high cholesterol content.

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