ABSTRACT:The exporter ABCC2 (cMOAT, MRP2) is a membrane-bound protein on the apical side of enterocytes and hepatic biliary vessels that transports leukotriene C 4 , glutathione, some conjugated bile salts, drugs, xenobiotics, and phytonutrients. The latter class includes quercetin, a bioactive flavonoid found in foods such as onions, apples, tea, and wine. There is no available three-dimensional (3D) structure of ABCC2. We have ABCC2 (cMOAT, MRP2) is a member of the family of ATP binding cassette (ABC) transporters. Lack of ABCC2 expression in humans leads to the Dubin-Johnson syndrome, an autosomal dominant hereditary disease (König et al., 1999). This disease is manifested by chronic hyperbilirubinemia due to reduced biliary secretion of bilirubin conjugates (Payen et al., 2002). ABCC2 is a transmembrane protein that uses the energy of ATP hydrolysis to translocate its substrates across biological membranes and transports a wide variety of compounds, including various endobiotics and xenobiotics. Recent studies suggest that ABCC2 influences oral bioavailability (Dietrich et al., 2003), and its inhibition decreases the elimination of xenobiotics. It is structurally closely related to ABCC1 (MRP1) and the substrate selectivities of ABCC1 and ABCC2 overlap (Gerk and Vore, 2002) to a large extent.The 1545-amino acid human ABCC2 contains two nucleotidebinding domains and up to 17 transmembrane helices distributed within three transmembrane domains (TMD), 1, 2, and 3. Classified in the same MRP family, human ABCC1 and human ABCC2 share 48% sequence identity as well as a similar membrane topology, implying structural and functional similarity. It has been shown that the aminoterminal TMD-1 of ABCC1 is not essential for substrate transport. Experimental efforts to characterize the substrate binding/transport have therefore been focused on transmembrane segments TM6 to TM17 of TMD-2 (TM6 to TM11) and TMD-3 (TM12 to TM17). To date, high-resolution 3D structures for ABCC1 and ABCC2 are still not available. The 3D structures for TMD-2 and -3 of ABCC1 have been obtained by homology modeling (Campbell et al., 2004). As revealed in the predicted 3D model, TMD-2 and -3 form a channel, which allows for the transportation of ABCC1 substrates. Together with biochemical studies, the 3D structural model for ABCC1 has provided further insight on the transport mechanisms (Campbell et al., 2004).Quercetin is an anticarcinogenic flavonoid that affects phase II
Codakine is an abundant 14-kDa mannose-binding C-type lectin isolated from the gills of the sea bivalve Codakia orbicularis. Binding studies using inhibition of hemagglutination indicated specificity for mannose and fucose monosaccharides. Further experiments using a glycan array demonstrated, however, a very fine specificity for N-linked biantennary complex-type glycans. An unusually high affinity was measured by titration microcalorimetry performed with a biantennary Asn-linked nonasaccharide. The crystal structure of the native lectin at 1.3 Å resolution revealed a new type of disulfide-bridged homodimer. Each monomer displays three intramolecular disulfide bridges and contains only one calcium ion located in the canonical binding site that is occupied by a glycerol molecule. The structure of the complex between Asn-linked nonasaccharide and codakine has been solved at 1.7 Å resolution. All residues could be located in the electron density map, except for the capping 1-4-linked galactosides. The ␣1-6-linked mannose binds to calcium by coordinating the O3 and O4 hydroxyl groups. The GlcNAc moiety of the ␣1,6 arm engages in several hydrogen bonds with the protein, whereas the GlcNAc on the other antenna is stacked against Trp 108 , forming an extended binding site. This is the first structural report for a bivalve lectin.Lectins are multivalent carbohydrate-binding proteins that play important roles in the social life of cells. A growing repertoire of lectins has been identified in invertebrates (1), where these molecules are involved in self/nonself recognition (2). For example, lectins play a role in aggregation mechanisms in corals and sponges (3) or in sperm-egg recognition in oysters (4). Lectin mediation of symbiosis with algae or bacteria has been observed in coral (5) and nematodes (6). Nevertheless, the most common function assessed for lectins in marine invertebrates is their role in innate immunity by specific binding of polysaccharide-coated pathogenic bacteria (7,8).Different lectins have been identified in bivalves and they most frequently belong to the C-type lectin family. Proteins from this group of calcium-dependent lectins have been reported in oysters (9, 10), scallops (11), and clams (12, 13). C-type lectins are characterized by a carbohydrate recognition domain (CRD) 3 with a conserved fold and the involvement of a calcium ion in carbohydrate binding (14). The crystal structure of mannose-binding protein was the first one to be described (15). The CRD belongs to a larger family sharing a common fold and is referred to as the C-type lectin-like domain (16).Codakine is a 14-kDa C-type lectin purified from the gill of the tropical clam Codakia orbicularis (Linné 1758) by affinity chromatography on a mannose-agarose column (17). It forms homodimers and heterodimers with isoforms 1 (NCBI accession number AAX19697) and 2 (NCBI accession number ABQ40396) (13). A 19-amino acid peptide signal suggests that the lectin travels through a secretory pathway. The 129-amino acid sequence of the mature ...
Human 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) catalyzes the interconversion of cortisone into active cortisol. 11betaHSD1 inhibition is a tempting target for the treatment of a host of human disorders that might benefit from blockade of glucocorticoid action, such as obesity, metabolic syndrome, and diabetes type 2. Here, we report an in silico screening study aimed at identifying new selective inhibitors of human 11betaHSD1 enzyme. In the first step, homology modeling was employed to build the 3D structure of 11betaHSD1. Further, molecular docking was used to validate the predicted model by showing that it was able to discriminate between known 11betaHSD1 inhibitors or substrates and non-inhibitors. The homology model was found to reproduce closely the crystal structure that became publicly available in the final stages of this work. Finally, we carried out structure-based virtual screening experiments on both the homology model and the crystallographic structure with a database of 114,000 natural molecules. Among these, 15 molecules were consistently selected as inhibitors based on both the model and crystal structures of the enzyme, implying a good quality for the homology model. Among these putative 11betaHSD1 inhibitors, two were flavonone derivatives that have already been shown to be potent inhibitors of the enzyme.
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