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81.
Georgsson J Rosenström U Wallinder C Beaudry H Plouffe B Lindeberg G Botros M Nyberg F Karlén A Gallo-Payet N Hallberg A 《Bioorganic & medicinal chemistry》2006,14(17):5963-5972
Two pentapeptides, Ac-Tyr-Ile-His-Pro-Phe/Ile, were synthesized and shown to have angiotensin II AT2 receptor affinity and agonistic activity. Based on these peptides, a new series of 13 pseudopeptides was synthesized via introduction of five different turn scaffolds replacing the Tyr-Ile amino acid residues. Pharmacological evaluation disclosed subnanomolar affinities for some of these compounds at the AT2 receptor. Substitution of Phe by Ile in this series of ligands enhanced the AT2 receptor affinity of all compounds. These results suggest that the C-terminal amino acid residues can be elaborated on to enhance the AT2 receptor affinity in truncated Ang II analogues. 相似文献
82.
A.K. Mahalingam Yiqian Wan A.M.S. Murugaiah Charlotta Wallinder Xiongyu Wu Bianca Plouffe Milad Botros Fred Nyberg Anders Hallberg Nicole Gallo-Payet Mathias Alterman 《Bioorganic & medicinal chemistry》2010,18(12):4570-4590
Structural alterations to the benzylic position of the first drug-like selective angiotensin II AT2 receptor agonist (1) have been performed, with the emphasis to reduce the CYP 450 inhibitory property of the initial structure. The imidazole moiety, responsible for the CYP 450 inhibitory effect in 1, was replaced with various heterocycles. In addition, the modes of attachment of the heterocycles, that is, carbon versus nitrogen attachment, and introduction of carbonyl functionalities to the benzylic position have been evaluated. In all the three series, AT2 receptor ligands with affinity in the lower nanomolar range were identified. None of the analogues, regardless of the substituents, exhibited any affinity for the AT1 receptor. Compounds with substantially reduced inhibition of the CYP 450 enzymes were obtained. Among them the compound 60 was found to induce neurite elongation in NG 108-15 cells and served as potent AT2 selective agonist. 相似文献
83.
Gunilla Hallberg Eva Andersson Tord Naessén Gunvor Ekman Ordeberg 《Reproductive biology and endocrinology : RB&E》2010,8(1):35
Background
In order to unravel the interactions between the epithelium and the extra cellular matrix (ECM) in breast tissue progressing to cancer, it is necessary to understand the relevant interactions in healthy tissue under normal physiologic settings. Proteoglycans in the ECM play an important role in the signaling between the different tissue compartments. The proteoglycan decorin is abundant in the breast stroma. Decreased expression in breast cancer tissue is a sign of a poor tumor prognosis. The heparane sulphate proteoglycans syndecan-1 and syndecan-4 promote the integration of cellular adhesion and proliferation. The aim of this study was to investigate the gene expression and location of decorin, syndecan-1 and syndecan-4 in the healthy breast during the menstrual cycle. 相似文献84.
Yasmin L Jansson AL Panahandeh T Palmer RH Francis MS Hallberg B 《The FEBS journal》2006,273(3):638-646
14-3-3 proteins belong to a family of conserved molecules expressed in all eukaryotic cells, which play an important role in a multitude of signaling pathways. 14-3-3 proteins bind to phosphoserine/phosphothreonine motifs in a sequence-specific manner. More than 200 14-3-3 binding partners have been found that are involved in cell cycle regulation, apoptosis, stress responses, cell metabolism and malignant transformation. A phosphorylation-independent interaction has been reported to occur between 14-3-3 and a C-terminal domain within exoenzyme S (ExoS), a bacterial ADP-ribosyltransferase toxin from Pseudomonas aeruginosa. In this study, we have investigated the effect of amino acid mutations in this C-terminal domain of ExoS on ADP-ribosyltransferase activity and the 14-3-3 interaction. Our results suggest that leucine-428 of ExoS is the most critical residue for ExoS enzymatic activity, as cytotoxicity analysis reveals that substitution of this leucine significantly weakens the ability of ExoS to mediate cell death. Leucine-428 is also required for the ability of ExoS to modify the eukaryotic endogenous target Ras. Finally, single amino acid substitutions of positions 426-428 reduce the interaction potential of 14-3-3 with ExoS in vitro. 相似文献
85.
Vernersson E Khoo NK Henriksson ML Roos G Palmer RH Hallberg B 《Gene expression patterns : GEP》2006,6(5):448-461
Anaplastic Lymphoma Kinase (ALK), a receptor tyrosine kinase, was first described as the fusion product causing a subtype of non-Hodgkin's lymphoma. To date Alk has been reported to be mainly expressed in CNS and other parts of the brain. Here we describe an extensive characterization of the mRNA and protein expression of ALK during mouse development. We show that mRNA and ALK protein show overlapping expressing patterns in specific regions of the central and the peripheral nervous systems. Furthermore, ALK is also expressed in the eye, nasal epithelium, olfactory nerve, tongue, skin, tissue surrounding the esophagus, stomach and midgut but not the hindgut. Expression of ALK is also found in testis and ovary. 相似文献
86.
YopE of Yersinia pseudotuberculosis inactivates three members of the small RhoGTPase family (RhoA, Rac1 and Cdc42) in vitro and mutation of a critical arginine abolishes both in vitro GTPase-activating protein (GAP) activity and cytotoxicity towards HeLa cells, and renders the pathogen avirulent in a mouse model. To understand the functional role of YopE, in vivo studies of the GAP activity in infected eukaryotic cells were conducted. Wild-type YopE inactivated Rac1 as early as 5 min after infection whereas RhoA was down regulated about 30 min after infection. No effect of YopE was found on the activation state of Cdc42 in Yersinia-infected cells. Single-amino-acid substitution mutants of YopE revealed two different phenotypes: (i) mutants with significantly lowered in vivo GAP activity towards RhoA and Rac1 displaying full virulence in mice, and (ii) avirulent mutants with wild-type in vivo GAP activity towards RhoA and Rac1. Our results show that Cdc42 is not an in vivo target for YopE and that YopE interacts preferentially with Rac1, and to a lesser extent with RhoA, during in vivo conditions. Surprisingly, we present results suggesting that these interactions are not a prerequisite to establish infection in mice. Finally, we show that avirulent yopE mutants translocate YopE in about sixfold higher amount compared with wild type. This raises the question whether YopE's primary function is to sense the level of translocation rather than being directly involved in downregulation of the host defence. 相似文献
87.
Food and feeding of juvenile turbot Scophthalmus maximus and flounder Pleuronectes flesus were studied in five nursery areas at Gotland, Central Baltic Sea, ICES SD 27 and SD 28. Ontogeny involved partitioning of available food resources. The food choice of turbot <30 mm standard length (LS) included both planktonic‐hyperbenthic prey (calanoid copepods and mysids) and epibenthic–endobenthic prey (chironomids and amphipods), whereas turbot ≥30 mm LS fed mainly on hyperbenthic species (mysids and fishes). Conversely, for flounder, epibenthic–endobenthic prey were the most abundant prey items throughout development (harpactocoid copepods, oligochaetes and chironomids for fish <40 mm LS and oligochaetes, chironomids and amphipods for flounder ≥40 mm LS). Thus, the highest degree of dietary overlap occurred between turbot <30 mm and flounder ≥40 mm. Food composition for both turbot and flounder varied, however, according to exposure and predominant wind direction in the nursery area. For example, expressed as the ratio between the biomass of mysids and fishes consumed, the relative importance of mysids v. fishes as food source for turbot, varied from <1 in the most sheltered area to 16 and 27 in the more open areas. Considerable differences in feeding incidence were recorded; mean ±s .d . 58 ± 20% for turbot <30 mm LS and 83 ± 8% for turbot ≥30 mm LS, as opposed to ≥85–90% for flounder irrespective of size. The lower feeding success of turbot <30 mm LS was related to mysid abundance, shown to vary spatially and temporally, and to density of flounder, indicating that food availability, and potentially interspecific competition, influence feeding of early juvenile turbot with implications for survival following settlement. Regarding variability in abundance, hyperbenthic prey, as mysids, are considered more variable than epi‐ and endobenthic organisms. Hence, in addition to the ‘nursery size hypothesis’, i.e. the positive relationship between abundance of recruits and extension of nursery areas, variability in food availability may explain the average lower recruitment of turbot as compared to other flatfishes, e.g. flounder. 相似文献
88.
Marinova Z Yakovleva T Melzig MF Hallberg M Nylander I Ray K Rodgers DW Hauser KF Ekström TJ Bakalkin G 《Biochemical and biophysical research communications》2004,321(1):202-209
A novel soluble non-opioid dynorphin A-binding factor (DABF) was identified and characterized in neuronal cell lines, rat spinal cord, and brain. DABF binds dynorphin A(1-17), dynorphin A(2-17), and the 32 amino acid prodynorphin fragment big dynorphin consisting of dynorphin A and B, but not other opioid and non-opioid peptides, opiates, and benzomorphans. The IC50 for dynorphin A(1-17), dynorphin A(2-17), and big dynorphin is in the 5-10 nM range. Using dynorphin A and big dynorphin fragments a binding epitope was mapped to dynorphin A(6-13). DABF has a molecular mass of about 70 kDa. SH-groups are apparently involved in the binding of dynorphin A since p-hydroxy-mercuribenzoic acid inhibited this process. Upon interaction with DABF dynorphin A was converted into Leu-enkephalin, which remained bound to the protein. These data suggest that DABF functions as an oligopeptidase that forms stable and specific complexes with dynorphin A. The presence of DABF in brain structures and other tissues with low level of prodynorphin expression suggests that DABF as an oligopeptidase may degrade other peptides. Dynorphin A at the sites of its release in the CNS may attenuate this degradation as a competitor when it specifically binds to the enzyme. 相似文献
89.
Mason MG Nicholls P Divne C Hallberg BM Henriksson G Wilson MT 《Biochimica et biophysica acta》2003,1604(1):47-54
Phanerochaete chrysosporium cellobiose oxidoreductase (CBOR) comprises two redox domains, one containing flavin adenine dinucleotide (FAD) and the other protoheme. It reduces both two-electron acceptors, including molecular oxygen, and one-electron acceptors, including transition metal complexes and cytochrome c. If the latter reacts with the flavin, the reduced heme b acts merely as a redox buffer, but if with the b heme, enzyme action involves a true electron transfer chain. Intact CBOR fully reduced with cellobiose, CBOR partially reduced by ascorbate, and isolated ascorbate-reduced heme domain, all transfer electrons at similar rates to cytochrome c. Reduction of cationic one-electron acceptors via the heme group supports an electron transfer chain model. Analogous reactions with natural one-electron acceptors can promote Fenton chemistry, which may explain evolutionary retention of the heme domain and the enzyme's unique character among secreted sugar dehydrogenases. 相似文献
90.
Hallberg B 《Biochemical Society transactions》2002,30(4):401-405
14-3-3 proteins belong to a family of conserved molecules, which play a regulatory role and participate in signal transduction and checkpoint control pathways. 14-3-3 proteins bind phosphoserine-phosphorylated ligands, such as the Raf-1 kinase and Bad, through recognition of the phosphorylated consensus motif, RSXpSXP (where pS is phosphoserine). Recently, a phosphorylation-independent interaction has been reported to occur between 14-3-3 and a small number of proteins, for example the 43 kDa inositol polyphosphate 5-phosphatase, glycoprotein Ib, p75NTR-associated cell-death executor (NADE) and the bacterial ADP-ribosyltransferase toxin exoenzyme S (ExoS). It has been suggested that specific residues of 14-3-3 proteins are required for activation of the bacterial toxin ExoS. An unphosphorylated peptide derived from a phage display library, known as the R18 peptide, and a synthetic peptide derived from ExoS inhibit the interaction between ExoS and 14-3-3. In this report we identify the amino acid sequence on ExoS which is responsible for its specific interaction with 14-3-3, both in vitro and in vivo. In addition, we believe that this interaction is critical for the ADP-ribosylation of an endogenous target, Ras, by ExoS both in vitro and in vivo. Loss of the 14-3-3-binding site on ExoS results in an ExoS molecule that is unable to efficiently inactivate Ras and shows a reduced capacity to change the morphology of infected cells, together with reduced killing activity. 相似文献