The structure of LC/A3 was found to be very similar to that of LC/A1, suggesting that the overall mode of SNAP-25 binding is common between these two proteins. However, circular dichroism (CD) thermal unfolding experiments demonstrated that LC/A3 is significantly less stable than LC/A1, implying that this might contribute to the reduced toxin persistence of BoNT/A3. These findings could be of interest in developing next-generation therapeutic toxins.Ras suppressor-1 (Rsu-1) is a leucine-rich repeat (LRR)-containing protein that is crucial for regulating cell adhesion and is involved in such physiological and pathological processes as focal adhesion assembly and tumor metastasis. Rsu-1 interacts with zinc-finger type multi-LIM domain-containing adaptor protein PINCH-1, known to be involved in the integrin-mediated consensus adhesome, but not with its highly homologous family member PINCH-2. However, the structural basis for and regulatory mechanisms of this specific interaction remain unclear. Here, we determined the crystal structures of Rsu-1 and its complex with the PINCH-1 LIM4-5 domains. Rsu-1 displays an arc-shaped solenoid architecture, with eight LRRs shielded by N- and C-terminal capping modules. We showed that the conserved concave surface of the Rsu-1 LRR domain binds and stabilizes the PINCH-1 LIM5 domain via salt bridge and hydrophobic interactions, while the C-terminal non-LIM region of PINCH-2 sterically disfavors Rsu-1 binding. We also showed that Rsu-1 can be assembled, via PINCH-1-binding, into a heteropentamer complex comprising Rsu-1, PINCH-1, ILK, Parvin, and Kindlin-2, which constitute a major consensus integrin adhesome crucial for focal adhesion assembly. Our mutagenesis and cell biological data emphasize the significance of the Rsu-1/PINCH-1 interaction in focal adhesion assembly and cell spreading, providing crucial molecular insights into Rsu-1-mediated cell adhesion with implications for disease development.Using a variety of activating and inhibitory receptors, natural killer (NK) cells protect against disease by eliminating cells that have downregulated class I major histocompatibility complex (MHC) proteins, such as in response to cell transformation or viral infection. The inhibitory murine NK receptor Ly49C specifically recognizes the class I MHC protein H-2Kb. Unusual among NK receptors, Ly49C exhibits a peptide-dependent sensitivity to H-2Kb recognition, which has not been explained despite detailed structural studies. To gain further insight into Ly49C peptide sensitivity, we examined Ly49C recognition biochemically and through the lens of dynamic allostery. We found that the peptide sensitivity of Ly49C arises through small differences in H-2Kb-binding affinity. Although molecular dynamics simulations supported a role for peptide-dependent protein dynamics in producing these differences in binding affinity, calorimetric measurements indicated an enthalpically as opposed to entropically driven process. A quantitative linkage analysis showed that this emerges from peptide-dependent dynamic tuning of electrostatic interactions across the Ly49C-H-2Kb interface. We propose a model whereby different peptides alter the flexibility of H-2Kb, which in turn changes the strength of electrostatic interactions across the protein-protein interface. Our results provide a quantitative assessment of how peptides alter Ly49C-binding affinity, suggest the underlying mechanism, and demonstrate peptide-driven allostery at work in class I MHC proteins. Lastly, our model provides a solution for how dynamic allostery could impact binding of some, but not all, class I MHC partners depending on the structural and chemical composition of the interfaces. The rise in consumption of dietary supplements containing the trace amines p-tyramine, p-synephrine and p-octopamine has been associated with cardiovascular side effects. Since renal blood flow plays an important role in blood pressure regulation, this study investigated the mechanisms of action of these trace amines on isolated porcine renal arteries. Contractile responses to amines were investigated in noradrenaline-depleted rings of porcine main renal arteries in the absence and presence of the α -adrenoceptor antagonist, prazosin (1μM), β-adrenoceptor antagonist, propranolol (1μM), or the trace amine-associated receptor (TAAR-1) antagonist, EPPTB (RO-5212773; 100nM or 100μM). All three amines induced constrictor responses of similar magnitude and potency. However, their mechanisms of action on the renal artery appeared to differ. Depleting endogenous noradrenaline stores significantly reduced maximum responses to tyramine and synephrine, but less for octopamine. When direct responses were examined on α1-adrenoceptors and possibly contractile TAAR (not TAAR-1). The two amines also activate simultaneous inhibitory responses via β-adrenoceptors, TAAR-1 and nitric oxide release. Diabetes and psychotic disorders are occasionally comorbid. Possible pathophysiologies linking these disorders include inflammation and oxidative stress. Glucagon like peptide-1 (GLP-1) agonists modulate glucose metabolism and may exert neuroprotective effects via central GLP-1 receptors. To explore the effects of GLP-1 agonist, liraglutide, on ketamine-induced hyper-locomotion and cognitive dysfunction and the associated inflammation and oxidative stress in normoglycemic and diabetic rats. Rats were divided into Chow fed (non-diabetic) and high fat diet fed/STZ (diabetic) groups I. non-diabetic/control, non-diabetic/liraglutide, non-diabetic/ketamine, non-diabetic/ketamine/liraglutide groups. II. diabetic/control, diabetic/liraglutide, diabetic/ketamine and diabetic/ketamine/liraglutide groups. Hyperlocomotion and cognitive dysfunction were assessed using open field and water maze tests. Biochemical parameters were measured in serum and hippocampus. Ketamine induced hyperlocomotion and cognitive dysfneficial effects of liraglutide on ketamine-induced hyperlocomotion and cognitive dysfunction are associated with reduction in TNF alpha and oxidative stress. Since effects of liraglutide occurred in diabetic and non-diabetic rats, glycemic and non-glycemic effects (via central GLP-1 receptors) might be involved. selleck chemicals Targeting oxidative stress and inflammation by GLP-1 agonists, may be a promising approach in psychotic patients with diabetes.