1,721,005 research outputs found
A commentary on the inhibition of human TPC2 channel by the natural flavonoid naringenin: methods, experiments, and ideas
Full text link: Human endo-lysosomes possess a class of proteins called TPC channels on their membrane, which are essential for proper cell functioning. This protein family can be functionally studied by expressing them in plant vacuoles. Inhibition of hTPC activity by naringenin, one of the main flavonoids present in the human diet, has the potential to be beneficial in severe human diseases such as solid tumor development, melanoma, and viral infections. We attempted to identify the molecular basis of the interaction between hTPC2 and naringenin, using ensemble docking on molecular dynamics (MD) trajectories, but the specific binding site remains elusive, posing a challenge that could potentially be addressed in the future by increased computational power in MD and the combined use of microscopy techniques such as cryo-EM
Unraveling the metabolic activities of bioactive compounds on cellular models of hepatosteatosis and adipogenesis through docking analysis with PPARs
No full textAbstract Obesity is associated with fatty liver disease. Available therapies show modest efficacy, and nutraceuticals with good effectiveness and safety are largely investigated. We focused on five natural compounds, three plant phenolic compounds (carvacrol, rosmarinic acid, silybin), and two thyroid hormones (T2: 3,5-diiodo-l-thyronine; T3: 3,5,3’-triiodo-L-thyronine) as comparison, to assess their beneficial effects on two cellular models of hepatosteatosis and adipogenesis. All compounds ameliorated the lipid accumulation and oxidative stress in both models, but with different potencies. The peroxisome proliferator-activated receptors (PPARs) are pivotal controllers of adipogenesis and lipid metabolism. For the main isoforms, PPARγ and PPARa, we assessed their possible binding to the compounds by molecular docking calculations, and their expression pattern by real-time PCR. All compounds bind both PPARs with different affinity, while not all compounds affect their expression. The results may clarify the distinctive molecular mechanisms underlying the action of the five compounds in the different cell models with possible applications to treat obesity
The Discovery of Naringenin as Endolysosomal Two-Pore Channel Inhibitor and Its Emerging Role in SARS-CoV-2 Infection
Full text linkThe flavonoid naringenin (Nar), present in citrus fruits and tomatoes, has been identified as a blocker of an emerging class of human intracellular channels, namely the two-pore channel (TPC) family, whose role has been established in several diseases. Indeed, Nar was shown to be effective against neoangiogenesis, a process essential for solid tumor progression, by specifically impairing TPC activity. The goal of the present review is to illustrate the rationale that links TPC channels to the mechanism of coronavirus infection, and how their inhibition by Nar could be an efficient pharmacological strategy to fight the current pandemic plague COVID-19
Computer simulations of biomolecules: the case of the N-terminal PrP Cu binding site
No full textLa proteina prionica umana lega gli ioni Cu+2 nel dominio
octarepeat della coda N-terminale fino a raggiungere una
occupazione piena ad un pH = 7,4. Recenti esperimenti mostrano che
il sotto-dominio HGGG dell'octarepeat é responsabile del mantenere
il metallo legato in una configurazione planare quadrata.
Utilizzando simulazioni di dinamica molecolare ab initio a partire
da principi primi del tipo di Car Parrinello, viene studiata la
coordinazione del Cu ai siti leganti della regione degli
octarepeat della proteina prionica. Sono state condotte
simulazioni per una serie di siti leganti strutturati. Sono
presentati risultati per i complessi Cu(HGGGW)(acqua), Cu(HGGG),
[Cu(HGGG)]2 and Cu(HGGG) + un imidazolo. Mentre la presenza di un
residuo Trp e di una molecola d'acqua non sembra influenzare la
natura della coordinazione del Cu, tutte le simulazioni confermano
una grande stabilitá del legame fra il Cu e gli azoti amidici
delle Gly deprotonate. In effetti si mostra che la deprotonazione
della Gly é energeticamente accessibile anche a basse temperature.
Nel caso dell'interessante complesso [Cu(HGGG)]2 risulta la
formazione di una configurazione intrecciata dei due domini con lo
scambio dei legami con gli azoti amidici fra i due centri Cu, in
maniera consistente con la corta distanza Cu-Cu osservata
sperimentalmente nel caso di piena occupazione. In presenza di piú
anelli imidazolici (uno dall'His e uno aggiunto al sistema) si
trova che il legame con gli azoti amidici dalle Gly deprotonate é
favorito. Questo é a priori sorprendente data l'alta affinitá
dell'imidazolo per il Cu.The human prion protein binds Cu+2 ions in the octarepeat domain
of the N-terminal tail up to full occupancy at pH = 7,4. Recent
experiments show that the HGGG octarepeat sub-domain is
responsible for holding the metal bound in a square planar
configuration. By using first principle ab initio molecular
dynamics simulations of the Car-Parrinello type, the coordination
of Cu to the binding sites of the prion protein octarepeat region
is investigated. Simulations are carried out for a number of
structured binding sites. Results for the complexes
Cu(HGGGW)(wat), Cu(HGGG), [Cu(HGGG)]2 and Cu(HGGG) + one imidazole
ring are presented. While the presence of a Trp residue and a
water molecule does not seem to affect the nature of the Cu
coordination, high stability of the bond between Cu and the amide
nitrogen of deprotonated Gly's is confirmed in all cases.
Actually, it is found that Gly deprotonation is energetically
accessible even at low temperatures. For the interesting
[Cu(HGGG)]2 complex a dynamically entangled arrangement of the two
domains with exchange of amide nitrogen bonds between the two Cu
centers emerges, which is consistent with the short Cu-Cu distance
observed in experiments at full Cu occupancy. In the presence of
multiple imidazole ring (one from the His and one added to the
system), it is found that the bond with the amide nitrogens from
deprotonated Gly's is favoured. This is a priori surprising given
the high affinity of imidazole for Cu
Normal mode calculation and infrared spectroscopy of proteins in water solution: Relationship between amide I transition dipole strength and secondary structure
Full text linkDipole Strength (DS) of the amides has gained a renewed interest in chemical physics since it provides an
important tool to disclose the on-site vibrational energy distributions. Apart from earlier experimental efforts on
polypeptides, little is still known about DS in complex proteins. We accurately measured the Fourier Transform
Infrared absorption spectra of nine proteins in water solution obtaining their Molar Extinction Coefficient in the
amide I and II spectral region. Our results show that the amide I DS value depends on the protein secondary
structure, being that of the α-rich and unstructured proteins lower by a factor of 2 than that of the β-rich proteins.
The average DS for amino acids in α and β secondary structures confirms this finding. Normal Mode calculation
and Molecular Dynamics were performed and used as tools for data analysis and interpretation. The present
outcomes corroborate the hypothesis that antiparallel β-sheet environment is more prone to delocalize the on-site
C=O stretching vibration through coupling mechanisms between carbonyl groups, whereas α-helix structures are
energetically less stable to permit vibrational mode delocalization
Infrared spectroscopy of SARS‐CoV‐2 viral protein. From receptor binding domain to spike protein
Full text linkSpike (S) glycoprotein is the largest structural protein of SARS-CoV-2 virus and the main one involved in anchoring of the host receptor ACE2 through the receptor binding domain (RBD). S protein secondary structure is of great interest for shedding light on various aspects, from functionality to pathogenesis, finally to spectral fingerprint for the design of optical biosensors. In this paper, the secondary structure of SARS-CoV-2 S protein and its constituting components, namely RBD, S1 and S2 regions, are investigated at serological pH by measuring their amide I infrared absorption bands through Attenuated Total Reflection Infrared (ATR-IR) spectroscopy. Experimental data in combination with MultiFOLD predictions, Define Secondary Structure of Proteins (DSSP) web server and Gravy value calculations, provide a comprehensive understanding of RBD, S1, S2, and S proteins in terms of their secondary structure content, conformational order, and interaction with the solvent
Conformational Dynamics of Lipoxygenases and Their Interaction with Biological Membranes
Full text linkLipoxygenases (LOXs) are a family of enzymes that includes different fatty acid oxygenases with a common tridimensional structure. The main functions of LOXs are the production of signaling compounds and the structural modifications of biological membranes. These features of LOXs, their widespread presence in all living organisms, and their involvement in human diseases have attracted the attention of the scientific community over the last decades, leading to several studies mainly focused on understanding their catalytic mechanism and designing effective inhibitors. The aim of this review is to discuss the state-of-the-art of a different, much less explored aspect of LOXs, that is, their interaction with lipid bilayers. To this end, the general architecture of six relevant LOXs (namely human 5-, 12-, and 15-LOX, rabbit 12/15-LOX, coral 8-LOX, and soybean 15-LOX), with different specificity towards the fatty acid substrates, is analyzed through the available crystallographic models. Then, their putative interface with a model membrane is examined in the frame of the conformational flexibility of LOXs, that is due to their peculiar tertiary structure. Finally, the possible future developments that emerge from the available data are discussed
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Monitoring Insulin-Aggregated Structures in the Presence of Epigallocatechin-3-gallate and Melatonin by Molecular Dynamics Simulations
No full textIn the present work we illustrate the results of classical molecular dynamics simulations of model systems composed of six insulin molecules in water in the presence and in the absence of either epigallocatechin-3-gallate or melatonin molecules. For each model system, we performed three independent simulations (replicas) to study the aggregate formation dynamics and insulin interaction with epigallocatechin-3-gallate and melatonin. We find that melatonin is less stably close to insulin with respect to epigallocatechin-3-gallate, which interacts more stably with insulin molecules and mainly with insulin's chain B hydrophobic residues. We observe that the shape of the insulin-aggregated structures in the three model systems is different and depends on whether epigallocatechin-3-gallate is present or not. Simulations show that in the absence of epigallocatechin-3-gallate, insulin molecules tend to form linear aggregates, while in the presence of epigallocatechin-3-gallate, aggregates display a globular shape, less prone to form fibril structures
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