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C─H⋯O hydrogen bonds constitute a unique class of cohesive interactions. Their properties are similar to those of canonical H‐bonds, although their energy is significantly lower, typically in the 0.5–2.5 kcal/mol range. Polarised C─H groups, such as those adjacent to electronegative groups, or within aromatic moieties, are particularly strong donors. C─H⋯O bonds are ubiquitous in nucleic acids and in proteins, notably stabilizing the β‐sheet secondary structure. They have also been observed in numerous protein‐ligand interactions. Here, we analysed crystal structures, deposited in the Protein Data Bank, of complexes of FDA‐approved protein kinase inhibitors with cognate kinases, to assess the possible role of C─Hinhibitor⋯Oprotein hydrogen bonds. The conserved hinge motif of protein kinases with two solvent‐exposed carbonyl groups and one exposed backbone amide, is well known to be involved in canonical H‐bonding with inhibitors. We now find that in virtually all complexes where the inhibitor interacts with the hinge backbone, at least one of the hinge carbonyl groups accepts an H‐bond from a C─H inhibitor group, which is either aromatic or adjacent to an electronegative group. These observations are important for design of hinge‐binding scaffolds of novel kinase inhibitors for therapeutic use. [ABSTRACT FROM AUTHOR]

Protein kinase C (PKC) and Protein kinase D (PKD) isoforms can sense diacylglycerol (DAG) generated in the different cellular compartments in various physiological processes. DAG accumulates in multiple organs of the obese subjects, which leads to the disruption of metabolic homeostasis and the development of diabetes as well as associated diseases. Multiple studies proved that aberrant activation of PKCs and PKDs contributes to the development of metabolic diseases. DAG-sensing PKC and PKD isoforms play a crucial role in the regulation of metabolic homeostasis and therefore might serve as targets for the treatment of metabolic disorders such as obesity and diabetes. [ABSTRACT FROM AUTHOR]

Platelets, originally described for their role in blood coagulation, are now also recognized as key players in modulating inflammation, tissue regeneration, angiogenesis, and carcinogenesis. Recent evidence suggests that platelets also influence insulin secretion from pancreatic β cells. The multifaceted functions of platelets are mediated by the factors stored in their alpha granules (AGs) and dense granules (DGs). AGs primarily contain proteins, while DGs are rich in small molecules, and both types of granules are released during blood coagulation. Specific components stored in AGs and DGs are implicated in various inflammatory, regenerative, and tumorigenic processes. However, the relative contributions of AGs and DGs to the regulation of pancreatic β cell function have not been previously explored. In this study, we utilized mouse models deficient in AG content (neurobeachin-like 2 (Nbeal2) -deficient mice) and models with defective DG release (Unc13d -deficiency in bone marrow-derived cells) to investigate the impact of platelet granules on insulin secretion from pancreatic β cells. Our findings indicate that AG deficiency has little to no effect on pancreatic β cell function and glucose homeostasis. Conversely, mice with defective DG release exhibited glucose intolerance and reduced insulin secretion. Furthermore, Unc13d -deficiency in hematopoietic stem cells led to a reduction in adipose tissue gain in obese mice. Obtained data suggest that DGs, but not AGs, mediate the influence of platelets on pancreatic β cells, thereby modulating glucose metabolism. • Dense granules mediate the influence of platelets on insulin secretion. • Deficiency of alpha granules in platelets has no effect on glucose homeostasis. • Unc13D deficiency in hemopoietic cells leads to reduced adiposity in mice. [ABSTRACT FROM AUTHOR]