Structural bases for blockade and activation of BK channels by Ba ions.

We studied the impact of Ba ions on the function and structure of large conductance potassium (BK) channels. Ion composition has played a crucial role in the physiological studies of BK channels due to their ability to couple ion composition and membrane voltage signaling. Unlike Ca, which activates BK channels through all (RCK) domains, Ba has been described as specifically interacting with the RCK2 domain.

Generation of antitumor chimeric antigen receptors incorporating T cell signaling motifs.

Chimeric antigen receptor (CAR) T cells have been used to successfully treat various blood cancers, but adverse effects have limited their potential. Here, we developed chimeric adaptor proteins (CAPs) and CAR tyrosine kinases (CAR-TKs) in which the intracellular ζ T cell receptor (TCRζ) chain was replaced with intracellular protein domains to stimulate signaling downstream of the TCRζ chain. CAPs contain adaptor domains and the kinase domain of ZAP70, whereas CAR-TKs contain only ZAP70 domains.

Establishment and Characterization of Amitrole-Induced Mouse Thyroid Adenomatous Nodule-Derived Cell Lines.

Thyroid cancer cell lines have been of great value for the study of thyroid cancer. However, the availability of benign thyroid adenoma cell lines is limited. Cell lines were established from thyroid adenomatous nodules that developed in mice treated with the goitrogen amitrole.

TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin.

Lung squamous cell carcinoma (LSCC) is the second most prevalent type of lung cancer. Despite extensive genomic characterization, no targeted therapies are approved for the treatment of LSCC. Distal amplification of the 3q chromosome is the most frequent genomic alteration in LSCC, and there is an urgent need to identify efficacious druggable targets within this amplicon.

Analysis of SARS-CoV-2 ORF3a structure reveals chloride binding sites.

SARS-CoV-2 ORF3a is believed to form ion channels, which may be involved in the modulation of virus release, and has been implicated in various cellular processes like the up-regulation of fibrinogen expression in lung epithelial cells, downregulation of type 1 interferon receptor, caspase-dependent apoptosis, and increasing IFNAR1 ubiquitination. ORF3a assemblies as homotetramers, which are stabilized by residue C133. A recent cryoEM structure of a homodimeric complex of ORF3a has been released.

Electrostatically Driven Guanidinium Interaction Domains that Control Hydrogel-Mediated Protein Delivery In Vivo.

Protein biologics are an important class of drugs, but the necessity for frequent parenteral administration is a major limitation. Drug-delivery materials offer a potential solution, but protein-material adsorption can cause denaturation, which reduces their effectiveness. Here, we describe a new protein delivery platform that limits direct contact between globular protein domains and material matrix, yet from a single subcutaneous administration can be tuned for long-term drug release.

The upcoming subatomic resolution revolution.

Subatomic resolution macromolecular crystallography has been revealing the most fascinating details of macromolecular structures for many years. This most extreme form of macromolecular crystallography is going through rapid changes. A new generation of superbrilliant X-ray sources and detectors is facilitating the rapid acquisition of high-quality datasets.

Conformational energy range of ligands in protein crystal structures: The difficult quest for accurate understanding.

In this review, we address a fundamental question: What is the range of conformational energies seen in ligands in protein-ligand crystal structures? This value is important biophysically, for better understanding the protein-ligand binding process; and practically, for providing a parameter to be used in many computational drug design methods such as docking and pharmacophore searches. We synthesize a selection of previously reported conflicting results from computational studies of this issue and conclude that high ligand conformational energies really are present in some crystal structures. The main source of disagreement between different analyses appears to be due to divergent treatments of electrostatics and solvation.

Nanoinformatics workshop report: Current resources, community needs, and the proposal of a collaborative framework for data sharing and information integration.

The quantity of information on nanomaterial properties and behavior continues to grow rapidly. Without a concerted effort to collect, organize and mine disparate information coming out of current research efforts, the value and effective use of this information will be limited at best. Data will not be translated to knowledge.

Inhibition of phosphoinositol 3 kinase contributes to nanoparticle-mediated exaggeration of endotoxin-induced leukocyte procoagulant activity.

Aim: Disseminated intravascular coagulation is an increasing concern for certain types of engineered nanomaterials. Recent studies have shed some light on the nanoparticle physicochemical properties contributing to this toxicity; however, the mechanisms are poorly understood. Leukocyte procoagulant activity (PCA) is a key factor contributing to the initiation of this toxicity.

Nanoinformatics: a new area of research in nanomedicine.

Over a decade ago, nanotechnologists began research on applications of nanomaterials for medicine. This research has revealed a wide range of different challenges, as well as many opportunities. Some of these challenges are strongly related to informatics issues, dealing, for instance, with the management and integration of heterogeneous information, defining nomenclatures, taxonomies and classifications for various types of nanomaterials, and research on new modeling and simulation techniques for nanoparticles.

Study of interaction energies between the PAMAM dendrimer and nonsteroidal anti-inflammatory drug using a distributed computational strategy and experimental analysis by ESI-MS/MS.

The structure of a dendrimer exhibits a large number of internal and superficial cavities, which can be exploited, to capture and deliver small organic molecules, enabling their use in drug delivery. Structure-based modeling and quantum mechanical studies can be used to accurately understand the interactions between functionalized dendrimers and molecules of pharmaceutical and industrial interest. In this study, we implemented a Metropolis Monte Carlo algorithm to calculate the interaction energy of dendrimer-drug complexes, which can be used for in silico prediction of dendrimer-drug affinity.

PDB ligand conformational energies calculated quantum-mechanically.

We present here a greatly updated version of an earlier study on the conformational energies of protein-ligand complexes in the Protein Data Bank (PDB) [Nicklaus et al. Bioorg. Med.

Nanoinformatics: an emerging area of information technology at the intersection of bioinformatics, computational chemistry and nanobiotechnology.

After the progress made during the genomics era, bioinformatics was tasked with supporting the flow of information generated by nanobiotechnology efforts. This challenge requires adapting classical bioinformatic and computational chemistry tools to store, standardize, analyze, and visualize nanobiotechnological information. Thus, old and new bioinformatic and computational chemistry tools have been merged into a new sub-discipline: nanoinformatics.

Supramolecular complexes of quantum dots and a polyamidoamine (PAMAM)-folate derivative for molecular imaging of cancer cells.

Polyamidoamine (PAMAM) dendrimers and water-soluble 3-mercaptopropionic acid (MPA)-capped CdSe quantum dots (QDs) were combined to produce a new gel containing supramolecular complexes of QDs/PAMAM dendrimers. The formation of the QDs/PAMAM supramolecular complexes was confirmed by high resolution electron microscopy and Fourier transform infrared (FTIR) analyses. Molecular dynamics simulations corroborated the structure of the new QDs/PAMAM-based supramolecular compound.

On the role of the SP1 domain in HIV-1 particle assembly: a molecular switch?

Expression of a retroviral protein, Gag, in mammalian cells is sufficient for assembly of immature virus-like particles (VLPs). VLP assembly is mediated largely by interactions between the capsid (CA) domains of Gag molecules but is facilitated by binding of the nucleocapsid (NC) domain to nucleic acid. We have investigated the role of SP1, a spacer between CA and NC in HIV-1 Gag, in VLP assembly.

Metal ions-stimulated iron oxidation in hydroxylases facilitates stabilization of HIF-1 alpha protein.

The exposure of cells to several metal ions stabilizes HIF-1 alpha protein. However, the molecular mechanisms are not completely understood. They may involve inhibition of hydroxylation by either substitution of iron by metal ions or by iron oxidation in the hydroxylases.

In-silico nanobio-design. A new frontier in computational biology.

Nanobiology is a fast-emerging discipline that brings the tools of nanotechnology to the biological sciences. The introduction of new techniques may accelerate the development of highly specific biomedical treatments, increase their efficiency, and minimize their side effects. Introducing foreign bodies into the complex machinery of the human body is, however, a great and humbling challenge, as past experience has shown.

Towards a consensus on datasets and evaluation metrics for developing B-cell epitope prediction tools.

A B-cell epitope is the three-dimensional structure within an antigen that can be bound to the variable region of an antibody. The prediction of B-cell epitopes is highly desirable for various immunological applications, but has presented a set of unique challenges to the bioinformatics and immunology communities. Improving the accuracy of B-cell epitope prediction methods depends on a community consensus on the data and metrics utilized to develop and evaluate such tools.

A new perspective in the Lewis acid catalyzed ring opening of epoxides. Theoretical study of some complexes of methanol, acetic acid, dimethyl ether, diethyl ether, and ethylene oxide with boron trifluoride.

Several 1:1, 1:2, and 2:2 complexes between BF3 and CH3OH (Met), CH3COOH (AcA), (CH3)2O (DME), (CH3CH2)2O (DEE), and (CH2)2O (EOX) have been studied using ab initio (MP2) and density functional theory (DFT) (PBE, B3LYP) methods and the 6-311++G(3df,2pd) basis set. Geometrical structures and vibrational frequencies are reported, in most cases, for the first time. A detailed comparison of the vibrational frequencies for the O.

Molecular structure and internal rotation in 2,3,5,6-tetrafluoroanisole as studied by gas-phase electron diffraction and quantum chemical calculations.

The geometric structure of 2,3,5,6-tetrafluoroanisole and the potential function for internal rotation around the C(sp2)-O bond were determined by gas electron diffraction (GED) and quantum chemical calculations. Analysis of the GED intensities with a static model resulted in near-perpendicular orientation of the O-CH3 bond relative to the benzene plane with a torsional angle around the C(sp2)-O bond of tau(C-O) = 67(15) degrees. With a dynamic model, a wide single-minimum potential for internal rotation around the C(sp2)-O bond with perpendicular orientation of the methoxy group [tau(C-O) = 90 degrees] and a barrier of 2.

Quantum chemical modeling of reaction mechanism for 2-oxoglutarate dependent enzymes: effect of substitution of iron by nickel and cobalt.

Enzymatic hydroxylation reactions carried out by 2-oxoglutarate (2OG) dependent iron-containing oxygenases were recently implicated in oxygen sensing. In addition to oxygen depletion, two metals, cobalt and nickel, are capable of inducing hypoxic stress in cells by inhibiting oxygenase activity. Two possible scenarios have been proposed for the explanation of the hypoxic effects of cobalt and nickel: oxidation of enzyme-bound iron following cobalt or nickel exposure, and substitution of iron by cobalt or nickel.