Search results for "binding"
showing 10 items of 3896 documents
Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits.
2015
The neural circuit mechanisms underlying the integration and functions of adult-born dentate granule cell (DGCs) are poorly understood. Adult-born DGCs are thought to compete with mature DGCs for inputs to integrate. Transient genetic overexpression of a negative regulator of dendritic spines, Kruppel-like factor 9 (Klf9), in mature DGCs enhanced integration of adult-born DGCs and increased NSC activation. Reversal of Klf9 overexpression in mature DGCs restored spines and activity and reset neuronal competition dynamics and NSC activation, leaving the DG modified by a functionally integrated, expanded cohort of age-matched adult-born DGCs. Spine elimination by inducible deletion of Rac1 in …
Designer Thiopurine-analogues for Optimised Immunosuppression in Inflammatory Bowel Diseases.
2015
Background and Aims: The clinical use of azathioprine and 6-mercaptopurine is limited by their delayed onset of action and potential side effects such as myelosuppression and hepatotoxicity. As these drugs specifically target the Vav1/Rac1 signalling pathway in T lamina propria lymphocytes via their metabolite 6-thio-GTP, we studied expression and optimised suppression of this pathway in inflammatory bowel diseases [IBD]. Methods: Rac1 and Vav1 expressions were analysed in mucosal immune cells in IBD patients. Targeted molecular modelling of the 6-thio-GTP molecule was performed to optimise Rac1 blockade; 44 modified designer thiopurine-analogues were tested for apoptosis induction, potenti…
Do genetic polymorphisms in angiotensin converting enzyme 2 (ACE2) gene play a role in coronavirus disease 2019 (COVID-19)?
2020
Abstract Although some demographic, clinical and environmental factors have been associated with a higher risk of developing coronavirus disease 2019 (COVID-19) and progressing towards severe disease, altogether these variables do not completely account for the different clinical presentations observed in patients with comparable baseline risk, whereby some subjects may remain totally asymptomatic, whilst others develop a very aggressive illness. Some predisposing genetic backgrounds can hence potentially explain the broad inter-individual variation of disease susceptibility and/or severity. It has been now clearly established that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2…
The Role of Adrenoceptors in the Retina
2020
The retina is a part of the central nervous system, a thin multilayer with neuronal lamination, responsible for detecting, preprocessing, and sending visual information to the brain. Many retinal diseases are characterized by hemodynamic perturbations and neurodegeneration leading to vision loss and reduced quality of life. Since catecholamines and respective bindings sites have been characterized in the retina, we systematically reviewed the literature with regard to retinal expression, distribution and function of alpha1 (α1)-, alpha2 (α2)-, and beta (β)-adrenoceptors (ARs). Moreover, we discuss the role of the individual adrenoceptors as targets for the treatment of retinal diseases.
Antiprotozoal and cysteine proteases inhibitory activity of dipeptidyl enoates
2018
A family of dipeptidyl enoates has been prepared and tested against the parasitic cysteine proteases rhodesain, cruzain and falcipain-2 related to sleeping sickness, Chagas disease and malaria, respectively. They have also been tested against human cathepsins B and L1 for selectivity. Dipeptidyl enoates resulted to be irreversible inhibitors of these enzymes. Some of the members of the family are very potent inhibitors of parasitic cysteine proteases displaying k2nd (M−1s−1) values of seven orders of magnitude. In vivo antiprotozoal testing was also performed. Inhibitors exhibited IC50 values in the micromolar range against Plasmodium falciparum, Trypanosoma brucei, Trypanosoma cruzi and ev…
Structural and functional insights into lysostaphin–substrate interaction
2018
Lysostaphin from Staphylococcus simulans and its family enzymes rapidly acquire prominence as the next generation agents in treatment of S. aureus infections. The specificity of lysostaphin is promoted by its C-terminal cell wall targeting domain selectivity towards pentaglycine bridges in S. aureus cell wall. Scission of these cross-links is carried out by its N-terminal catalytic domain, a zinc-dependent endopeptidase. Understanding the determinants affecting the efficiency of catalysis and strength and specificity of interactions lies at the heart of all lysostaphin family enzyme applications. To this end, we have used NMR, SAXS and molecular dynamics simulations to characterize lysostap…
A Perspective : Active Role of Lipids in Neurotransmitter Dynamics
2019
AbstractSynaptic neurotransmission is generally considered as a function of membrane-embedded receptors and ion channels in response to the neurotransmitter (NT) release and binding. This perspective aims to widen the protein-centric view by including another vital component—the synaptic membrane—in the discussion. A vast set of atomistic molecular dynamics simulations and biophysical experiments indicate that NTs are divided into membrane-binding and membrane-nonbinding categories. The binary choice takes place at the water-membrane interface and follows closely the positioning of the receptors’ binding sites in relation to the membrane. Accordingly, when a lipophilic NT is on route to a m…
Stability of OBPs
2020
Odorant binding proteins (OBPs) are small proteins, some of which bind odorants with high specificity. OBPs are relatively easy to produce and show a pronounced stability toward thermal and chemical denaturation. This high stability renders OBPs attractive candidates for the development of odorant detections systems. Unfortunately, binding of odorants is not easy to quantify due to lack of spectroscopic signals upon binding. Therefore, a possible approach to detect binding is to employ the shift in thermal or chemical stability upon ligand-protein interaction. Being a rather indirect approach, the experimental setup should be done with care. Here, the experimental results on stability of OB…
Radiolabeling of a polypeptide polymer for intratumoral delivery of alpha-particle emitter, 225Ac, and beta-particle emitter, 177Lu
2021
Introduction: Radiotherapy of cancer requires both alpha- and beta-particle emitting radionuclides, as these radionuclide types are efficient at destroying different types of tumors. Both classes of radionuclides require a vehicle, such as an antibody or a polymer, to be delivered and retained within the tumor. Polyglutamic acid (pGlu) is a polymer that has proven itself effective as a basis of drug-polymer conjugates in the clinic, while its derivatives have been used for pretargeted tumor imaging in a research setup. trans-Cyclooctene (TCO) modified pGlu is suitable for pretargeted imaging or therapy, as well as for intratumoral radionuclide therapy. In all cases, it becomes indirectly ra…
Native Electrospray-based Metabolomics Enables the Detection of Metal-binding Compounds
2019
AbstractMetals are essential for the molecular machineries of life, and microbes have evolved a variety of small molecules to acquire, compete for, and utilize metals. Systematic methods for the discovery of metal-small molecule complexes from biological samples are limited. Here we describe a two-step native electrospray ionization mass spectrometry method, in which double-barrel post-column metal-infusion and pH adjustment is combined with ion identity molecular networking, a rule-based informatics workflow. This method can be used to identify metal-binding compounds in complex samples based on defined mass (m/z) offsets of ion features with the same chromatographic profiles. As this nati…