Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The affinity of a flexible ligand that adopts a specific conformation when bound to its receptor should be increased with the appropriate use of conformational restraints. By determining the structure of protein-ligand complexes, such restraints can in principle be designed into the bound ligand in a rational way. A tricyclic variant (TCsA) of the immunosuppressant cyclosporin A (CsA), which inhibits the proliferation of T lymphocytes by forming a cyclophilin-CsA-calcineurin complex, was designed with the known three-dimensional structure of a cyclophilin-CsA complex. The conformational restraints in TCsA appear to be responsible for its greater affinity for cyclophilin and calcineurin relative to CsA.
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PMID:Structure-based design of a cyclophilin-calcineurin bridging ligand. 821 Nov 44

Previous studies have suggested that gangliosides have an important role in cell signaling and recognition. However, their specific function in these processes has not been clearly defined. A mAb, R24, that reacts specifically with a cell surface ganglioside (GD3) has been demonstrated to stimulate proliferation of T cells derived from human peripheral blood. In this study, we have investigated the mechanisms by which the R24 mAb affects T cell functions. We have observed that the R24 mAb stimulates GD3+ T cell proliferation, cytotoxicity, and surface marker expression of IL-2R alpha-chain, IL-2R beta-chain, HLA-DR, CD11a, and CD11c. Additionally, IFN-gamma activity but not IL-1, IL-2, or IL-4 activity was present in culture supernatants 72 h after R24 stimulation. In some donors, increased IL-6 and TNF-alpha activity also was detected after R24 treatment. Furthermore, R24 treatment resulted in translocation of c-rel, but little or no NF kappa B p50 or p65, from the cytoplasm to the nucleus and an increase of NF kappa B binding complexes containing c-rel and p50. This treatment also caused increased tyrosine phosphorylation of specific protein substrates. R24-stimulated increases in proliferation, cytotoxicity, and cell surface protein expression could be blocked by cyclosporin and staurosporin, indicating that cyclophilin/calcineurin and protein kinase C may be involved in the R24 signaling pathway. Additionally, herbimycin A, a tyrosine kinase inhibitor, blocked the R24-stimulated increase in proliferation but not cytotoxicity at concentrations consistent with specificity for tyrosine kinases. These results suggest that multiple biochemical pathways are involved in the activation of human T cells by R24.
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PMID:Increased proliferation, cytotoxicity, and gene expression after stimulation of human peripheral blood T lymphocytes through a surface ganglioside (GD3) 828 32

Cyclosporin A, a calcineurin inhibitor, was administered into the rat hippocampus. Seven days after drug administration the effects of phosphatase activity suppression in the brain to changes in neuronal cytoskeletal proteins were studied. Rat brain homogenates injected with cyclosporin A showed 16-38% suppression of Ca/calmodulin-dependent phosphatase activity measured by 32P released from 32P-labeled histone, indicating that cyclosporin A acts as an inhibitor of calcineurin after binding with cyclophilin in the brain. Hematoxylin-eosin staining revealed many basophilic neurons in the pyramidal layer of hippocampus, cerebellum, thalamus and cerebral cortex. Immunohistochemical study with anti-phosphorylated neurofilament 200kDa antibody showed positive staining of neuronal perikarya of these basophilic neurons. The number of immunopositive neurons with anti-phosphorylated neurofilament 200KDa increased with the concentration of cyclosporin A injected into the brain, indicating a dose-dependent effect of the compound. Staining with anti-dephosphorylated neurofilament 200KDa (SMI-32) was decreased in neuronal perikarya of cyclosporin A injected brains compared with that of control brains injected with dimethyl sulfoxide alone, suggesting an increased phosphorylation of neurofilament 200KDa subunit protein. The perikarya of these basophilic neurons were not stained with anti-PHF (paired helical filaments) or anti-tau antibodies. Immunostaining with anti-ubiquitin was not increased in these cells. Immunostaining with anti-calcineurin A and anti-calcineurin B showed positive staining of neurons in hippocampus, cerebellum and caudate nucleus both in experimental and control brains. Calcineurin B immunoreactivity was more intense in pyramidal cells in hippocampus injected with cyclosporin A than in controls. Western blot study with antibody against calcineurin A revealed significantly more degradation products of calcineurin A in cyclosporin A injected brains. The present data suggest that cyclosporin A inhibits calcineurin activity in the brain, which results in increased phosphorylation of perikaryal neurofilaments. Since abnormal phosphorylation is speculated in the pathological process of Alzheimer's disease, the results will help elucidate the participation of phosphatase in the pathology of cytoskeletal proteins in Alzheimer's disease.
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PMID:Phosphorylated neurofilament accumulation in neuronal perikarya by cyclosporin A injection in rat brain. 838 21

Cyclosporin A, a cyclic undecapeptide, is a potent immunosuppressant that binds to a peptidyl-prolyl cis-trans isomerase of 165 amino acids, cyclophilin. The cyclosporin A/cyclophilin complex inhibits the calcium- and calmodulin-dependent phosphatase, calcineurin, resulting in a failure to activate genes encoding interleukin-2 and other lymphokines. The three-dimensional structures of uncomplexed cyclophilin, a tetrapeptide/cyclophilin complex, and cyclosporin A when bound to cyclophilin have been reported. However, the structure of the cyclosporin A/cyclophilin complex has not been determined. Here we present the solution structure of the cyclosporin A/cyclophilin complex obtained by heteronuclear three-dimensional NMR spectroscopy. The structure, one of the largest determined by NMR, differs from proposed models of the complex and is analysed in terms of the binding interactions and structure/activity relationships for CsA analogues.
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PMID:Solution structure of the cyclosporin A/cyclophilin complex by NMR. 842

Human cyclophilin A (CypA), a ubiquitous intracellular protein of 165 amino acids, is the major receptor for the cyclic undecapeptide immunosuppressant drug cyclosporin A (CsA), which prevents allograft rejection after transplant surgery and is efficacious in the field of autoimmune diseases. CsA prevents T-cell proliferation by blocking the calcium-activated pathway leading to interleukin-2 transcription. Besides their ability to bind CsA, the cyclophilin isoforms also have peptidyl-prolyl isomerase activity and enhance the rate of protein folding. The macrolide FK506 acts similarly to CsA and its cognate receptor FKBP also has peptidyl-prolyl isomerase activity. Inhibition of this enzymatic activity alone is not sufficient to achieve immunosuppression. A direct molecular interaction between the drug-immunophilin complex (CsA-CypA, or FK506-FKBP) and the phosphatase calcineurin, is responsible for modulating the T-cell receptor signal transduction pathway. Here we describe the crystal structure of a decameric CypA-CsA complex. The crystallographic asymmetric unit is composed of a pentamer of 1:1 cyclophilin-cyclosporin complexes of rather exact non-crystallographic fivefold symmetry. The 2.8 A electron density map is of high quality. The five independent cyclosporin molecules are clearly identifiable, providing an unambiguous picture of the detailed interactions between a peptide drug and its receptor. It broadly confirms the results of previous NMR, X-ray and modelling studies, but provides further important structural details which will be of use in the design of drugs that are analogues of CsA.
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PMID:X-ray structure of a decameric cyclophilin-cyclosporin crystal complex. 842 1

Calcineurin (CaN) is a calcium- and calmodulin-dependent protein serine/threonine phosphate which is critical for several important cellular processes, including T-cell activation. CaN is the target of the immunosuppressive drugs cyclosporin A and FK506, which inhibit CaN after forming complexes with cytoplasmic binding proteins (cyclophilin and FKBP12, respectively). We report here the crystal structures of full-length human CaN at 2.1 A resolution and of the complex of human CaN with FKBP12-FK506 at 3.5 A resolution. In the native CaN structure, an auto-inhibitory element binds at the Zn/Fe-containing active site. The metal-site geometry and active-site water structure suggest a catalytic mechanism involving nucleophilic attack on the substrate phosphate by a metal-activated water molecule. In the FKBP12-FK506-CaN complex, the auto-inhibitory element is displaced from the active site. The site of binding of FKBP12-FK506 appears to be shared by other non-competitive inhibitors of calcineurin, including a natural anchoring protein.
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PMID:Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex. 852 2

Cyclosporin A (CSA), a potent immunosuppressive drug, has recently been shown to bind with high affinity to the immunophilin, cyclophilin. Calcineurin, the calcium-dependent protein phosphatase, binds the cyclophilin/CSA complex, rendering it inactive and blocking dephosphorylation of phosphoproteins. Very high concentrations of cyclophilin have been reported in the brain with a localization identical to that of calcineurin. We have reported that interleukin-2 (IL-2) releases corticotropin-releasing hormone (CRH) by generation of nitric oxide (NO). Nitric oxide synthase (NOS), the enzyme in nitric oxidergic neurons that converts arginine into citrulline plus NO, is inactive in the phosphorylated state. We hypothesized that cyclosporin might therefore inhibit IL-2-induced acute CRH release by blocking the dephosphorylation of NOS by calcineurin. Consequently, we examined the effect of CSA on the release of CRH from mediobasal hypothalami (MBH) in vitro in 'basal' conditions and in the presence of IL-2, which we had previously shown to stimulate CRH release acutely in this preparation. Incubation of MBH for 30 min with IL-2 (10(-13) M), the concentration that was most effective in previous experiments, evoked a significant release of CRH. CSA at 10(-6) or 10(-8) M did not alter basal release of CRH; however, addition of either concentration completely blocked the IL-2-induced release of CRH. This acute action of CSA within the brain is probably mediated by blockade of the dephosphorylation of NOS by calcineurin.
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PMID:Cyclosporin A inhibits interleukin-2-induced release of corticotropin-releasing hormone. 852 89

Cyclosporin A (CsA) acts as a powerful immunosuppressant through its binding to the cytosolic isomerase, cyclophilin (CyP), forming a complex which inhibits the phosphatase activity of calcineurin. The drug is also selectively anti-parasitic but its mode of action remains unknown. The mouse tapeworm, Hymenolepis microstoma is sensitive to CsA, but the rat tapeworm, H. diminuta is not susceptible either in rats, mice or in vitro. Using these two tapeworm models, the uptake and binding of CsA were examined in relation to parasite cyclophilins. Uptake and compartmentalization of the drug were markedly different in the two species: H. microstoma takes up more drug than does H. diminuta and sequesters more drug into intracellular compartments. Characterization of cyclophilins using both CsA binding and isomerase activity assays reveals that H. microstoma possesses two cyclophilin isoforms (M(r) 17,700 and 21,400) with isomerase activity that is inhibited by CsA. using identical assays, we have been unable to demonstrate CsA-binding proteins or CsA-sensitive isomerase activity in H. diminuta. These data suggest that the anthelmintic action of CsA relates in some way to the presence and function of parasite cyclophilins.
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PMID:Hymenolepis diminuta and H. microstoma: uptake of cyclosporin A and drug binding to parasite cyclophilins. 855 92

Mammalian mitochondria possess an inner membrane channel, the permeability transition pore (MTP), which can be inhibited by nanomolar concentrations of cyclosporin (CS) A. The molecular basis for MTP inhibition by CSA remains unclear. Mitochondria also possess a matrix cyclophilin (CyP) with a unique N-terminal sequence (CyP-M). To test the hypothesis that it interacts with the MTP, we have studied the interactions of CyP-M with rat liver mitochondria by Western blotting with a specific antibody against its unique N terminus. Although sonication in isotonic sucrose at pH 7.4 refraction sediments with submitochondrial particles at 150,000 x g. We show that the interactions of this CyP-M pool with submitochondrial particles are disrupted (i) by the addition of CSA, which inhibits the pore, but not of CSH, which does not, and (ii) by acidic pH condition, which also leads to selective inhibition of the MTP; furthermore, we show that the effect of acidic pH on CyP-M fully prevents the inhibitory effect of H+ on the MTP (Nicolli, A., Petronilli, V., and Bernardi, P. (1993) Biochemistry 32, 4461-4465). These data suggest that CyP-M inhibition by CSA and protons may be due to unbinding of CyP-M from its putative binding site on the MTP. A role for CyP-M in MTP regulation is also supported by a study with a series of CSA derivatives with graded affinity for CyP. We show that with each derivative the isomerase activity of CyP-M purified to homogeneity is similar to that displayed at inhibition of MTP opening, CyP-M (but not CyP-A) and decreased efficiency at MTP inhibition is obtained by substitution in position 8 while a 4-substituted, nonimmunosuppressive derivative is a as effective as the native CSA molecule, indicating that calcineurin is not involved in MTP inhibition by CSA.
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PMID:Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and cyclosporin A-sensitive channel. 856 77

A program, MOLMAKER, is described which, in conjunction with a 2D-3D conversion program and 3D database software, can generate de novo 3D databases to aid in drug design. MOLMAKER is based upon graph-theoretical techniques for vertex degree set generation and constructive enumeration of molecular graphs. The generated molecular graphs are then functionalised in a probabilistic manner but in accordance with various constraints specified by the user. The resulting connection tables can be converted into 3D structures by commercial software and loaded into a 3D database for pharmacophore searching. The utility of MOLMAKER is illustrated by two examples of interest from the recent scientific literature: the design of novel protein kinase C agonists and of a bridging ligand for cyclophilin-calcineurin.
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PMID:MOLMAKER: de novo generation of 3D databases for use in drug design. 857 88


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