Exploring an Intracellular Allosteric Site of CC-Chemokine Receptor 4 from 3D Models, Probe Simulations, and Mutagenesis.

We applied our previously developed probe confined dynamic mapping protocol, which combines enhanced sampling molecular dynamics (MD) simulations and fragment-based approaches, to identify the binding site of GSK2239633A (-[[3-[[3-[(5-chlorothiophen-2-yl)sulfonylamino]-4-methoxyindazol-1-yl]methyl]phenyl]methyl]-2-hydroxy-2-methylpropanamide), a selective CC-chemokine receptor type 4 (CCR4) negative allosteric modulator, using CCR4 homology and AlphaFold models. By comparing the performance across five computational models, we identified conserved (K310 and Y304) and non-conserved (M243) residue hotspots for GSK2239633A binding, which were validated by mutagenesis and bioluminescence resonance energy transfer assay. Further analysis of 3D models and MD simulations highlighted the pair of residues 6.

Changed regulation of granulocyte NADPH oxidase activity in the mouse model of obesity-induced type 2 diabetes mellitus.

NADPH oxidase is a target of hyperglycemia in type 2 diabetes mellitus (T2DM), which causes dysregulation of enzyme. Alterations in regulation of NADPH oxidase activity mediated receptor and non-receptor signaling in bone marrow granulocytes of mice with obesity-induced T2DM were studied. The animals fed high fat diet (516 kcal/100 g) for 16 weeks.

Structural basis for the ligand recognition and signaling of free fatty acid receptors.

Free fatty acid receptors 1 to 4 (FFA1 to FFA4) are class A G protein-coupled receptors (GPCRs). FFA1 to FFA3 share substantial sequence similarity, whereas FFA4 is unrelated. However, FFA1 and FFA4 are activated by long-chain fatty acids, while FFA2 and FFA3 respond to short-chain fatty acids generated by intestinal microbiota.

Morphology and Phase Compositions of FePt and CoPt Nanoparticles Enriched with Noble Metal.

The article reveals for the first time the features of nanoparticle morphology, phase compositions, and their changes when heating FePt and CoPt nanoalloys. Nanoparticles were obtained by co-reduction of precursor solution mixtures with hydrazine hydrate. The features were found by a complex of methods of X-ray diffraction (in situ XRD and X-ray scattering), TEM HR, and cyclic voltammetry.

β-Arrestin-dependent and -independent endosomal G protein activation by the vasopressin type 2 receptor.

The vasopressin type 2 receptor (VR) is an essential G protein-coupled receptor (GPCR) in renal regulation of water homeostasis. Upon stimulation, the VR activates Gα and Gα, which is followed by robust recruitment of β-arrestins and receptor internalization into endosomes. Unlike canonical GPCR signaling, the β-arrestin association with the VR does not terminate Gα activation, and thus, Gα-mediated signaling is sustained while the receptor is internalized.