Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The phospholipid selectivity of protein kinase C (PKC) activation was examined by using two substrates, histone and a random copolymer of lysine and serine [poly(lysine, serine)] (PLS), plus phospholipids provided as vesicles or as Triton-mixed micelle preparations. The results indicated that substrate-phospholipid interaction was an essential component of PKC activation and that many in vitro properties of PKC activation are attributable to this interaction. The substrate histone interacted with phospholipid-Triton mixed micelles containing phosphatidylserine (PS), but not with those containing phosphatidylinositol (PI) or phosphatidylglycerol (PG). In direct correlation, only PS-Triton mixed micelles were effective in supporting PKC activity. Also, the minimum PS composition (4 mol % in Triton) required to induce significant histone-PS interaction coincided with the minimum composition required for phosphorylation of histones. Moreover, the PS composition required for maximum activity varied with the histone concentration of the reaction. In contrast to histone, PLS interacted with phospholipid-Triton mixed micelles containing either PS, PI, or PG, and all these mixed micelles supported the phosphorylation of PLS. In fact, by selection of appropriate experimental conditions (e.g., concentration of substrate and phospholipid), any of the three mixed micelles could appear the most effective in supporting PKC activity. Phospholipid vesicles containing PS, PG, or PI were found to interact with both histone and PLS and to support the activity of PKC. Physical properties of the solution and conditions used for preparation of phospholipid vesicles had considerable influence on PKC activation. At high phospholipid concentrations, vesicles containing PS, PI, or PG supported the activity of PKC to essentially the same level, provided that the physical differences among the phospholipid vesicles were minimized.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of substrate in determining the phospholipid specificity of protein kinase C activation. 347 93

The role of substrate in influencing the cofactor requirements of the phospholipid- and Ca2+-dependent protein kinase C (PKC) was investigated by using several substrates. All of the substrates tested, including histone, troponin I, myosin light chain, protamine, poly(arginine, serine) (PAS), poly(lysine, serine) (PLS), and myelin basic protein (MBP), were found to interact with and aggregate phospholipid vesicles as well as phosphatidylserine (PS)-Triton mixed micelles. Phosphorylation of these different substrates by PKC indicated the presence of three distinct substrate categories: substrates such as protamine requiring no cofactors; substrates such as PLS, PAS, and MBP requiring only the presence of phospholipid; and substrates such as histone, myosin light chain, and troponin I requiring the presence of Ca2+ and phospholipid. Diacylglycerol was a major cofactor only with category C substrates. These different requirements correlated with the interaction of the substrate with phospholipid and/or enzyme. The substrates in category A interacted strongly with and aggregated PKC in a binary mixture. In the absence of Ca2+, PKC bound to substrates of category B directly but not to substrates in category C. Thus, substrate-enzyme binding eliminated the Ca2+ requirement of phosphorylation, and aggregation of substrate-enzyme complex eliminated the phospholipid requirements as well. Substrate-phospholipid interaction and substrate phosphorylation were inhibited by increasing salt concentrations, but the amount needed depended upon the substrate. Loss of PKC activity appeared to coincide with loss of substrate-PS aggregation while dissociation of PKC from the membranes required much higher salt concentrations. Poly(L-lysine) and poly(L-arginine), two potent inhibitors of PKC, also showed substrate-dependent inhibition characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of substrate in imparting calcium and phospholipid requirements to protein kinase C activation. 359 3

The current work was conducted to investigate the effectiveness of two conceptually distinct in silico ligand-based tools: Partial Least Squares Discriminant Analysis (PLS-DA) and 3D similarity, including shape, physico-chemical and electrostatics to classify target-specific pharmacophores with enrichment power for selective GSK-3 inhibitors against the phylogenetically related CDK-2, CDK-4, CDK-5 and PKC. All virtual screens were performed on four data sets of targets matched pairwise, including selective and nonselective inhibitors for GSK-3. The classification method PLS-DA results revealed that all obtained models are statistically robust according to the cross-validation and response permutation tests. Regarding selective GSK-3 inhibitors differentiation in terms of selectivity (Se), specificity (Sp), and accuracy (ACC), the PLS-DA models for CDK-4/GSK-3, and PKC/GSK-3 datasets are highly efficient discriminative. 3D similarity searches for CDK-4/GSK-3, PKC/GSK-3, and CDK-2/GSK-3 datasets using the most selective reference molecules lead to highest enrichments of selective GSK-3 inhibitors. EON yields excellent early and overall enrichments for ET_ST and ET_combo for most selective query for CDK-4/GSK-3. CDK-5/GSK-3 dataset didn't show consistent statistically significant enrichments for 3D similarity virtual screening. The current methodology is reliable and could be used as a powerful tool for the detection of potentially selective molecules targeting GSK-3.
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PMID:Partial Least Squares Discriminant Analysis and 3D Similarity Perspective Applied to Analyze Comprehensively the Selectivity of Glycogen Synthase Kinase 3 Inhibitors. 3194