Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P17931 (galectin-3)
 2,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polysaccharides are possibly involved in the pharmacological effects of Viscum album (mistletoe) extracts, which are used in cancer therapy. Therefore the water-soluble polysaccharides of the fresh plant and the fermented proprietary preparation Iscador were isolated and characterized inter alia by methylation analysis, partial hydrolysis and C-13-NMR spectroscopy. The main polysaccharide of the green parts of Viscum is a highly esterified galacturonan whereas in Viscum 'berries' a complex arabinogalactan is predominant. Both types of these constituents were found in Iscador but with definite changes in molecular weight and structure. An interaction between the arabinogalactan and the galactose-specific lectin (ML I) in Viscum could be demonstrated. In three immunological tests (granulocyte, chemiluminescence, carbon clearance test) the polysaccharides failed to increase phagocytic activity of granulocytes and macrophages.
 ...
PMID:Structure and properties of polysaccharides from Viscum album (L.). 380 77

Manganese superoxide dismutase (MnSOD) of Aspergillus fumigatus, a fungus involved in many pulmonary complications, has been identified as IgE-binding protein. It has been shown also that MnSODs from other organisms, including human, are recognized by IgE Abs from individuals sensitized to A. fumigatus MnSOD. Comparison of the fungal and the human crystal structure should allow the identification of structural similarities responsible for IgE-mediated cross-reactivity. The three-dimensional structure of A. fumigatus MnSOD has been determined at 2-A resolution by x-ray diffraction analysis. Crystals belonged to space group P2(1)2(1)2(1) with unit cell dimensions of a = 65.88 A, b = 98.7 A, and c = 139.28 A. The structure was solved by molecular replacement using the structure of the human MnSOD as a search model. The final refined model included four chains of 199-200 amino acids, four manganese ions, and 745 water molecules, with a crystallographic R-factor of 19.4% and a free R-factor of 23.3%. Like MnSODs of other eukaryotic organisms, A. fumigatus MnSOD forms a homotetramer with the manganese ions coordinated by three histidines, one aspartic acid, and one water molecule. The fungal and the human MnSOD share high similarity on the level of both primary and tertiary structure. We identified conserved amino acids that are solvent exposed in the fungal and the human crystal structure and are therefore potentially involved in IgE-mediated cross-reactivity.
 ...
PMID:Comparison of the crystal structures of the human manganese superoxide dismutase and the homologous Aspergillus fumigatus allergen at 2-A resolution. 1180 64

The X-ray structure of mistletoe lectin I (MLI), a type-II ribosome-inactivating protein (RIP), cocrystallized with galactose is described. The model was refined at 3.0 A resolution to an R-factor of 19.9% using 21 899 reflections, with Rfree 24.0%. MLI forms a homodimer (A-B)2 in the crystal, as it does in solution at high concentration. The dimer is formed through contacts between the N-terminal domains of two B-chains involving weak polar and non-polar interactions. Consequently, the overall arrangement of sugar-binding sites in MLI differs from those in monomeric type-II RIPs: two N-terminal sugar-binding sites are 15 A apart on one side of the dimer, and two C-terminal sugar-binding sites are 87 A apart on the other side. Galactose binding is achieved by common hydrogen bonds for the two binding sites via hydroxy groups 3-OH and 4-OH and hydrophobic contact by an aromatic ring. In addition, at the N-terminal site 2-OH forms hydrogen bonds with Asp27 and Lys41, and at the C-terminal site 3-OH and 6-OH undergo water-mediated interactions and C5 has a hydrophobic contact. MLI is a galactose-specific lectin and shows little affinity for N-acetylgalactosamine. The reason for this is discussed. Structural differences among the RIPs investigated in this study (their quaternary structures, location of sugar-binding sites, and fine sugar specificities of their B-chains, which could have diverged through evolution from a two-domain protein) may affect the binding sites, and consequently the cellular transport processes and biological responses of these toxins.
 ...
PMID:Crystal structure at 3 A of mistletoe lectin I, a dimeric type-II ribosome-inactivating protein, complexed with galactose. 1282 44

Nonylphenol, an estrogenic xenobiotic widely used in the manufacture of plastics and detergents, has been found in drinking water and may therefore enter the body through the oral route. Thus, intestinal cells lining the alimentary tract serve as the body's first line of defense against this compound. In this study, the effects of nonylphenol on the human intestinal cell line Caco-2 were determined using transepithelial electrical resistance (TEER) measurement and proteomics. Results show that 10 microM nonylphenol can disrupt the tight-junction permeability of Caco-2 cells in approximately 15 min. Incubating the cells with 1 or 10 microM nonylphenol for 6 days resulted in the enhanced expressions of galectin-3 (approximately 4-fold vs. control with 1 microM; 2-fold with 10 microM), glutathione S-transferase A2 (approximately 8-fold with 1 microM; 5-fold with 10 microM) and peroxiredoxin-1 (approximately 6-fold with 1 microM; 4-fold with 10 microM). These expressions may represent a possible consortium of mechanisms by which the cells protect themselves against nonylphenol-induced stresses. To the best of our knowledge, this is the first study on the effects of nonylphenol on Caco-2 cells.
 ...
PMID:Expressions of galectin-3, glutathione S-transferase A2 and peroxiredoxin-1 by nonylphenol-incubated Caco-2 cells and reduction in transepithelial electrical resistance by nonylphenol. 1605 31

Dynamic combinatorial library design exploiting the thiol-disulfide exchange readily affords access to glycosyldisulfides. In order to reveal lectin-binding properties of this type of non-hydrolyzable sugar derivative, libraries originating from a mixture of common building blocks of natural glycans and thiocompounds were tested against three plant agglutinins with specificity to galactose, fucose or N-acetylgalactosamine, respectively, in a solid-phase assay. Extent of lectin binding to matrix-immobilized neoglycoprotein presenting the cognate sugar could be reduced, and evidence for dependence on type of carbohydrate was provided by dynamic deconvolution. Glycosyldisulfides also maintained activity in assays of increased physiological relevance, that is, using native tumor cells and also adding to the test panel an endogenous lectin (galectin-3) involved in tumor spread and cardiac dysfunction. N-Acetylgalactosamine was pinpointed as the most important building block of libraries for the human lectin and the digalactoside as most potent compound acting on the toxic mistletoe agglutinin which is closely related to the biohazard ricin. Because this glycosyldisulfide, which even surpasses lactose in inhibitory capacity, rivals thiodigalactoside as inhibitor, their degrees of intramolecular flexibility were comparatively analyzed by computational calculations. Molecular dynamics runs with explicit consideration of water molecules revealed a conspicuously high degree of potential for shape alterations by the disulfide's three-bond system at the interglycosidic linkage. The presented evidence defines glycosyldisulfides as biologically active ligands for lectins.
 ...
PMID:Glycosyldisulfides from dynamic combinatorial libraries as O-glycoside mimetics for plant and endogenous lectins: their reactivities in solid-phase and cell assays and conformational analysis by molecular dynamics simulations. 1678 46

Aromatic lactose 2-O-esters were synthesized and used to probe arene-arginine interactions with the galectin family of proteins. They were found to be low microM inhibitors of galectin-1, -3, and -9N-terminal domain and moderate inhibitors of galectin-7, but not inhibitors of galectin-8N-terminal, which lacks an arginine residue close to the critical, esterified lactose 2-O-position. Molecular modeling of galectins in complex with aromatic lactose 2-O-esters, as well as binding studies with a galectin-3 R186S mutant, confirmed that the inhibitory efficiency of the lactose 2-O-esters was due to the formation of strong interactions between the aromatic ester moieties and the arginine guanidinium groups of galectin-1 and -3. An important common feature shared by galectin-1 and -3 was that the arginines formed in-plane ion pairs with two side-chain carboxylates, which resulted in extended planar pi-electron surfaces that did not require solvation by water; these surfaces were ideal for stacking with aromatic moieties of the ligands. The results provide a basis for the design of lectin inhibitors and drugs that exploit interactions with arginine side-chains via aromatic moieties, which are involved in intramolecular protein salt bridges.
 ...
PMID:Studies of arginine-arene interactions through synthesis and evaluation of a series of galectin-binding aromatic lactose esters. 1763 64

The effects of effluent from a wastewater treatment plant (EWWTP) on intestinal epithelial Caco-2 cells, a human intestinal epithelial cell line derived from a human colon carcinoma, were investigated. Previous studies have shown that the wastewater constituents nonylphenol and lipopolysaccharide (LPS) induce the overexpression of specific proteins (galectin-3, glutathione S-transferase A2 subunit, peroxiredoxin-1, and heat shock protein 90, beta (HSP90b)). In this study, the first screening of EWWTP was carried out using the HSP47-transformed cell assay, which is a highly sensitive toxicity assay. From the results of proteomics analysis of human intestinal Caco-2 cells treated with EWWTP, we found the overexpression of specific proteins, namely, elongation factor 1beta and enolase 1. These results suggest that specific proteins can be used as biomarkers for the risk assessment of water and wastewater.
 ...
PMID:Toxicity assessment of wastewater by proteomics analysis. 1838 13

In this minireview, we examine the ability of modified citrus pectin (MCP), a complex water soluble indigestible polysaccharide obtained from the peel and pulp of citrus fruits and modified by means of high pH and temperature treatment, to affect numerous rate-limiting steps in cancer metastasis. The anti-adhesive properties of MCP as well as its potential for increasing apoptotic responses of tumor cells to chemotherapy by inhibiting galectin-3 anti-apoptotic function are discussed in the light of a potential use of this carbohydrate-based substance in the treatment of multiple human malignancies.
 ...
PMID:Modified citrus pectin anti-metastatic properties: one bullet, multiple targets. 1906 92

Formation of protein ligand complexes is a fundamental phenomenon in biochemistry. During the process, significant solvent reorganization is produced along the contact surface and many water molecules strongly bound to the protein's ligand binding site must be displaced. Both the thermodynamics and kinetics of this process are complex and a clear understanding at the microscopic level has been not achieved so far. Special attention has been paid to the structure of water molecules on carbohydrate recognition sites of various proteins, and many studies support the idea that displacement of these water molecules should have a crucial effect on the binding free energy. Molecular dynamics (MD) simulations in explicit water solvent is a very promising approach for this type of studies. Using MD simulations combined with statistical mechanics analysis, thermodynamic properties of these water molecules can be computed and analyzed in a comparative view. Using this idea, we developed a set of analysis tools to link solvation with ligand binding in a key carbohydrate binding protein, human galectin-1 (hGal-1). Specifically, we defined water sites (WS) in terms of the thermodynamic properties of water molecules strongly bound to protein surfaces. In the present work, we selected a group of proteins whose ligand bound complexes have been already structurally characterized in order to extend the analysis of the role of the surface associated water molecules in the ligand binding and recognition process. The selected proteins are concanavalin-A (Con-A), galectin-3 (Gal-3), cyclophilin-A (Cyp-A), and two modules CBM40 and CBM32 of the multimodular bacterial sialidase. Our results show that the probability of finding water molecules inside the WS, p(v), with respect to the bulk density is directly correlated to the likeliness of finding an hydroxyl group of the ligand in the protein-ligand complex. This information can be used to analyze in detail the solvation structure of the carbohydrate recognition domain (CRD) and its relation to the possible protein ligand complexes and suggests addition of OH-containing functional groups to displace water from high p(v) WS to enhance drugs, specially glycomimetic-drugs, protein affinity, and/or specificity.
 ...
PMID:Carbohydrate-binding proteins: Dissecting ligand structures through solvent environment occupancy. 1948 80

We study how the results of molecular dynamics (MD) simulations are affected by various choices during the setup, e.g., the starting velocities, the solvation, the location of protons, the conformation of His, Asn, and Gln residues, the protonation and titration of His residues, and the treatment of alternative conformations. We estimate the binding affinity of ligands to four proteins calculated with the MM/GBSA method (molecular mechanics combined with a generalized Born and surface area solvation energy). For avidin and T4 lysozyme, all variations gave similar results within 2 kJ/mol. For factor Xa, differences in the solvation or in the selection of alternative conformations gave results that are significantly different from those of the other approaches by 4-6 kJ/mol, whereas for galectin-3, changes in the conformations, rotations, and protonation gave results that differed by 10 kJ/mol, but only if residues close to the binding site were modified. This shows that the results of MM/GBSA calculations are reasonably reproducible even if the MD simulations are set up with different software. Moreover, we show that the sampling of phase space can be enhanced by solvating the systems with different equilibrated water boxes, in addition to the common use of different starting velocities. If different conformations are available in the crystal structure, they should also be employed to enhance the sampling. Protonation, ionization, and conformations of Asn, Gln, and His may also be used to enhance sampling, but great effort should be spent to obtain as reliable predictions as possible close to the active site.
 ...
PMID:A comparison of different initialization protocols to obtain statistically independent molecular dynamics simulations. 2113 39


1 2 3 4 5 Next >>