Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Structurally guided design approaches to low-molecular-weight platelet aggregation antagonists addressing the platelet-associated heterodimeric cell surface receptor gpIIb/IIIa rely on comparative studies of an ensemble of conformationally and biologically characterized compounds, since no high-resolution structure of the receptor system is available. We report a classical indirect and comparative pharmacophore refinement approach based on a series of small cyclic Arg-Gly-Asp (RGD) peptides as gpIIb/IIIa-fibrinogen interaction antagonists. These peptides have previously been investigated as potent and selective tumor cell adhesion inhibitors. The definition of geometrical descriptors classifying the RGD peptide conformations and their subsequent analysis over selected RGD- and RXD-containing protein structures allows for a correlation of distinct structural features for platelet aggregation inhibition. An almost parallel alignment of the Arg and Asp side chains was identified by a vector analysis as being present in all active cyclic hexa- and pentapeptides. This orientation is induced mainly by the constraint of backbone cyclization and is not of any covalent tripeptide-inherent origin, which was rationalized by a 500 ps high-energy MD simulation of a sequentially related linear model peptide. The incorporation of the recognition tripeptide Arg-Gly-Asp into the cyclic peptide templates acted as a filter mechanism, restricting the otherwise free torsional relation of both side chains to a parallel orientation. Based on the derived results, several detailed features of the receptor binding site could be deduced in terms of receptor complementarity. These findings should govern the design of next-generation compounds with enhanced activities. Furthermore, the complementary stereochemical characteristics of the substrate can be used as boundary conditions for pseudoreceptor modelling studies that are capable of reconstructing a hypothetical binding pocket, qualitatively resembling the steric and electronic demands of gpIIb/IIIa. It is interesting to note that these features provide clear differentiation to requirements for inhibition of alpha v beta 3 substrate binding. This can account for the extremely high selectivity and activity of some of our constrained peptides for either the alpha IIb beta 3 or the alpha v beta 3 receptor.
J Comput Aided Mol Des 1994 Dec
PMID:Pharmacophore refinement of gpIIb/IIIa antagonists based on comparative studies of antiadhesive cyclic and acyclic RGD peptides. 773 6

The cDNA of a novel mouse cell surface receptor (tie2) has been isolated from a mouse lung library. The predicted amino acid sequence of tie2 encodes a protein of 1122 amino acids, with an extracellular domain and an intracellular tyrosine kinase domain bisected by a transmembrane region. The extracellular domain consists of two Ig-like domains, three cysteine-rich domains and three fibronectin type III repeats whilst the intracellular tyrosine kinase domain has a short insert region of 15 amino acids. In vitro transcription/translation of the tie2 cDNA demonstrates that it encodes a glycoprotein of some 145 kDa. The tie2 protein exhibits a high degree of similarity to the cell surface receptor tie, (Partanen, J. et al., (1992) Mol. Cell. Biol., 12, 1698-1707), and together with this protein defines a new class of cell surface receptor.
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PMID:tie2, a putative protein tyrosine kinase from a new class of cell surface receptor. 821 21

NG2 is a membrane-associated chondroitin sulfate proteoglycan with a core protein of 300 kD. Previously it was shown immunochemically that the core protein of NG2 can bind type VI collagen (Stallcup, W., Dahlin, K., and P. Healy. 1990. J. Cell Biol. 111:3177-3188). We have extended our studies on the interaction of NG2 and type VI collagen by transfecting cells with the full-length rat NG2 cDNA. B28 rat neural cells and U251MG human glioma cells used for transfection do not synthesize NG2. Both cell lines secrete type VI collagen into tissue culture medium but do not anchor it at the cell surface. Upon transfection of these cells with the NG2 cDNA, NG2 was correctly localized to the cell surface. Furthermore, type VI collagen could now be detected on the surface of NG2-positive cells in a pattern that coincided with that of NG2. This ability of NG2 to anchor type VI collagen to the cell surface could be abolished by incubating the cells in the presence of anti-NG2 monoclonal antibodies. These findings indicate that NG2 functions as a cell surface receptor for type VI collagen and may play a role in modulating the assembly of pericellular matrix.
Mol Biol Cell 1993 Nov
PMID:Expression of NG2 proteoglycan causes retention of type VI collagen on the cell surface. 830 32

Prolactin receptor (PRLr) expression and distribution in thymus, spleen, bone marrow, lymph nodes, and peripheral blood lymphocytes from young adult Lewis rats are analyzed using single-color flow cytometry and a well-characterized monoclonal antibody directed against the rat liver PRLr. The in vivo effects of regional immunization on PRLr expression are also examined. PRLr is found to be widely distributed among cells of the immune system and demonstrates lymphoid tissue-specific patterns of expression. Footpad immunization caused the rapid, but transient, induction of PRLr expression in the draining lymph node, with only modest effects on PRLr expression in other distant lymphoid tissues. These studies indicate that PRL may be capable of direct interaction with the immune system through differential expression of the PRL cell surface receptor on select lymphoid target cell populations.
Mol Cell Endocrinol 1993 Apr
PMID:Prolactin receptor expression by lymphoid tissues in normal and immunized rats. 831 23

The bovine papillomavirus E5 gene encodes an oncoprotein that can independently transform rodent fibroblasts. This small 44-amino-acid protein is thought to function through the activation of growth factor receptors. E5 activation of the epidermal growth factor receptor results in an increase in the number of activated receptors at the cell surface. This finding suggests that E5 may act by inhibiting the normal down regulation of activated epidermal growth factor receptor via coated pit-mediated endocytosis. We have constructed a fusion protein consisting of glutathione S-transferase and the conserved C-terminal domain of E5 (GST-E5) in order to identify E5-associated cellular proteins that may be involved in its transforming activity. We have identified a 125-kDa cellular protein with a strong associated serine kinase activity that specifically associated with GST-E5 in the reduced form but not with GST-E5 fusions that contained changes in several conserved amino acids. Microsequence and biochemical analyses suggest that p125 is a novel member of the alpha-adaptin family. Since alpha-adaptins have previously been shown to be involved in coated pit-mediated cell surface receptor endocytosis and down regulation, these results suggest that p125 may be an alpha-adaptin-like molecule involved in growth factor receptor down regulation and that E5 may act by inhibiting its activity.
Mol Cell Biol 1993 Oct
PMID:The conserved C-terminal domain of the bovine papillomavirus E5 oncoprotein can associate with an alpha-adaptin-like molecule: a possible link between growth factor receptors and viral transformation. 841 45

A carboxyl-terminus truncated mutant of the guanine nucleotide-binding (G) protein-coupled TRH receptor (TRH-R) was previously shown to exhibit constitutive, i.e. TRH-independent, activity (C335Stop TRH-R). Chlordiazepoxide (CDE), a known competitive inhibitor of TRH binding to wild-type (WT) TRH-Rs, is shown to compete for binding to C335Stop TRH-Rs also. More importantly, CDE is shown to be a negative antagonist of C335Stop TRH-Rs. CDE rapidly caused the basal rate of inositol phosphate second messenger (IP) formation to decrease in AtT-20 pituitary cells stably expressing C335Stop TRH-Rs (AtT-C335Stop cells), but not in cells expressing WT TRH-Rs (AtT-WT cells). Similar observations were made in HeLa cells transiently expressing C335Stop or WT TRH-Rs. CDE inhibition of IP formation was shown to be specific for TRH-Rs using GH4C1 cells expressing both TRH-Rs and receptors for bombesin. In these cells, CDE inhibited TRH-stimulated IP formation, but had no effect on bombesin-stimulated IP formation. The effects of chronic administration of CDE were studied. Preincubation of AtT-C335Stop cells, but not AtT-WT cells, with CDE for several hours caused an increase in cell surface receptor number (up-regulation) that led to increased TRH stimulation of inositol phosphate formation and elevation of intracellular free Ca2+. Preincubation with CDE did not affect methyl-TRH binding affinity or TRH potency in cells expressing AtT-C335Stop or in AtT-WT cells. We conclude that CDE is a negative antagonist of C335Stop TRH-Rs and that constitutively active C335Stop TRH-Rs are down-regulated in AtT-20 pituitary cells in the absence of agonist.
Mol Endocrinol 1995 Nov
PMID:A constitutively active mutant thyrotropin-releasing hormone receptor is chronically down-regulated in pituitary cells: evidence using chlordiazepoxide as a negative antagonist. 858 22

The steroid specificity of the cell surface progesterone receptor in human sperm was examined with the use of progesterone, testosterone, and androstane analogues. Many compounds were shown to be more effective than progesterone at increasing intracellular free calcium concentration, e.g., 2 alpha-methyl-17beta-methoxy-5 alpha-androstan-3-one. Several testosterone analogues were demonstrated to be antagonists of progesterone, e.g., 9(11)-dehydro-2 alpha,17alpha-dimethyltestosterone. The synthetic potent progestigens, norethynodrel, cyproterone acetate, norethindrone, and megestrol acetate, were found to be only weak stimulators of the sperm cell surface receptor. Furthermore, these compounds were shown to antagonize the effect of progesterone to elevate intracellular free calcium concentration in sperm. It is known that progesterone and some of its analogues bind to the intracellular progesterone nuclear receptor via the alpha-face of the steroid molecule. In stark contrast, it was concluded from the analysis of the steroid analogues examined on human sperm in this study that intimate contact exists between the effective progesterone analogues and the sperm cell surface progesterone receptor across the beta-face of the steroid C/D-ring "upper" edge (C11, C12, and C17). Positioning of the C21 methyl group is also critical for efficacy, and recognition of the steroid A-ring seems not to be involved.
Mol Pharmacol 1996 Apr
PMID:Unusual steroid specificity of the cell surface progesterone receptor on human sperm. 860 3

The Fas cell surface receptor belongs to the tumor necrosis factor receptor family and can initiate apoptosis in a variety of cell types. Using the Fas cytoplasmic domain as bait in a yeast two-hybrid screening, we isolated a mouse cDNA encoding a 205-amino-acid protein. Its predicted protein sequence shows 68% identity and 80% similarity with the sequence of recently described human Mort/FADD. This protein, most likely the mouse homolog of human FADD, associates with Fas in vivo only upon the induction of cell death. A fraction of this protein is highly phosphorylated at serine/threonine residues, with both phosphorylated and unphosphorylated forms being capable of binding to FAS. Stable expression of a truncated form of the Mort/FADD protein protects cells from Fas-mediated apoptosis by interfering with the wild-type protein-Fas interaction. Thus, mouse Mort/FADD is an essential downstream component that mediates Fas-induced apoptosis.
Mol Cell Biol 1996 Jun
PMID:A mouse Fas-associated protein with homology to the human Mort1/FADD protein is essential for Fas-induced apoptosis. 864 83

We analyzed the role of receptor internalization and recycling in muscarinic acetylcholine receptor (mAChR) desensitization and resensitization. Incubation of Chinese hamster ovary cells stably expressing the m4 mAChR with 1 mM carbachol for 1 hr reduced cell surface receptor number by 50-60% with no change in total receptor number. Pretreatment of the cells with 450 mM sucrose, which did not affect the ability of m4 receptors to inhibit forskolin-stimulated cAMP accumulation, completely blocked receptor internalization. On the other hand, the carbachol treatment reduced the ability of m4 receptors to inhibit cAMP accumulation in both sucrose-treated and untreated cells, with a similar onset and to a similar extent. The EC50 value for carbachol was increased approximately 10-fold, and maximal inhibition determined at 100 microM carbachol was reduced approximately 50%. In contrast, thrombin-induced inhibition of cAMP accumulation was not affected. Recycled receptors in cells not treated with sucrose remained refractory to carbachol stimulation for > or = 2 hr after agonist removal, even though cell surface receptor number had recovered completely within 1 hr. In contrast, resensitization of receptor function was very rapid in cells treated with sucrose. Ten minutes on removal of agonist, mAChRs in the plasma membrane of sucrose-treated cells were fully resensitized. Also, an internalization-defective m4 mAChR mutant, T399A, that was found to desensitize similar to the wild-type receptor, resensitized more rapidly than the wild-type receptor. We conclude that desensitization and resensitization of m4 mAChRs in Chinese hamster ovary cells can occur at the plasma membrane and that receptor internalization strongly delays the process of resensitization of desensitized receptors.
Mol Pharmacol 1996 Aug
PMID:Receptor internalization delays m4 muscarinic acetylcholine receptor resensitization at the plasma membrane. 870 Jan 52

The low density lipoprotein receptor-related protein (LRP) is a multifunctional cell surface receptor that binds to the protease inhibitor alpha 2-macroglobulin (alpha 2 M). LRP has also been identified as the apolipoprotein E (apoE) receptor that mediates lipid metabolism. Recently it has been reported that apoE4, one of three common isoforms of apoE, is a main risk factor of Alzheimer's disease (AD). Moreover, all three of these proteins are reported to accumulate in the senile plaques in the brains of Alzheimer's patients. To understand the roles of LRP in the normal development of the central nervous system (CNS) and in the pathogenesis of AD, we studied the developmental expression and localization of LRP mRNA in the CNS. We used Northern blot analysis to investigate the developmental profile of LRP mRNA in the rat brain. LRP mRNA was first detected as early as in 18-day-old embryonic rat brain and was continuously expressed thereafter. A particularly high level of expression of the mRNA was observed in the perinatal stage. We also determined the cellular distribution of LRP mRNA in the CNS of 20-day-old embryonic and 6-week-old adult rat brains by in situ hybridization using a digoxigenin-labeled antisense riboprobe to LRP mRNA. In the embryonic rat brain, LRP mRNA was highly expressed in most of the cells, mainly neurons and glial cells. In the adult rat, LRP mRNA was expressed mostly in neurons in both the brain and the spinal cord. These results suggest that LRP plays crucial roles in development of the brain.
Brain Res Mol Brain Res 1995 Oct
PMID:Expression and distribution of low density lipoprotein receptor-related protein mRNA in the rat central nervous system. 877 44


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