Recent items - Molecular Pharmacology
Equilibrium between Adenylyl Cyclase and Phosphodiesterase Patterns Adrenergic Agonist Dose-Dependent Spatiotemporal cAMP/Protein Kinase A Activities in Cardiomyocytes [ARTICLES]
19/08/2010 00:03
β-Adrenergic receptor induces cAMP/Protein kinase A (PKA) activation to regulate cardiac contraction. Using real-time fluorescence resonance energy transfer imaging for highly sensitive detection of cAMP and PKA activities, we show two distinct phases in isoproterenol dose-dependent responses in cardiomyocytes: a transient and dose-dependent increase in cAMP and PKA activities at lower concentrations from 10–12 to 10–8 M; and a saturated initial increases at higher concentratio [...]
19/08/2010 00:03
β-Adrenergic receptor induces cAMP/Protein kinase A (PKA) activation to regulate cardiac contraction. Using real-time fluorescence resonance energy transfer imaging for highly sensitive detection of cAMP and PKA activities, we show two distinct phases in isoproterenol dose-dependent responses in cardiomyocytes: a transient and dose-dependent increase in cAMP and PKA activities at lower concentrations from 10–12 to 10–8 M; and a saturated initial increases at higher concentratio [...]
Genome-wide Expression Profiling Revealed Peripheral Effects of Cannabinoid Receptor 1 Inverse Agonists in Improving Insulin Sensitivity and Metabolic Parameters [ARTICLES]
19/08/2010 00:03
Inhibition of cannabinoid receptor 1 (CB1) has shown efficacy in reducing body weight and improving metabolic parameters, with the effects correlating with target engagement in the brain. The peripheral effects of inhibiting the CB1 receptor has been appreciated through studies in diet-induced obese and liver-specific CB1 knockout mice. In this article, we systematically investigated gene expression changes in peripheral tissues of diet-induced obese mice treated with the CB1 inverse agonist AM [...]
19/08/2010 00:03
Inhibition of cannabinoid receptor 1 (CB1) has shown efficacy in reducing body weight and improving metabolic parameters, with the effects correlating with target engagement in the brain. The peripheral effects of inhibiting the CB1 receptor has been appreciated through studies in diet-induced obese and liver-specific CB1 knockout mice. In this article, we systematically investigated gene expression changes in peripheral tissues of diet-induced obese mice treated with the CB1 inverse agonist AM [...]
Allosteric Inhibition of the Regulator of G Protein Signaling-G{alpha} Protein-Protein Interaction by CCG-4986 [ARTICLES]
19/08/2010 00:03
Regulator of G protein signaling (RGS) proteins act to temporally modulate the activity of G protein subunits after G protein-coupled receptor activation. RGS proteins exert their effect by directly binding to the activated G subunit of the G protein, catalyzing the accelerated hydrolysis of GTP and returning the G protein to its inactive, heterotrimeric form. In previous studies, we have sought to inhibit this GTPase-accelerating protein activity of the RGS protein by using small molecules. In [...]
19/08/2010 00:03
Regulator of G protein signaling (RGS) proteins act to temporally modulate the activity of G protein subunits after G protein-coupled receptor activation. RGS proteins exert their effect by directly binding to the activated G subunit of the G protein, catalyzing the accelerated hydrolysis of GTP and returning the G protein to its inactive, heterotrimeric form. In previous studies, we have sought to inhibit this GTPase-accelerating protein activity of the RGS protein by using small molecules. In [...]
Molecular Determinants for Competitive Inhibition of {alpha}4{beta}2 Nicotinic Acetylcholine Receptors [ARTICLES]
19/08/2010 00:03
The Erythrina alkaloids erysodine and dihydro-β-erythroidine (DHβE) are potent and selective competitive inhibitors of 4β2 nicotinic acetylcholine receptors (nAChRs), but little is known about the molecular determinants of the sensitivity of this receptor subtype to inhibition by this class of antagonists. We addressed this issue by examining the effects of DHβE and a range of aromatic Erythrina alkaloids on [3H]cytisine binding and receptor function in conjunction with homo [...]
19/08/2010 00:03
The Erythrina alkaloids erysodine and dihydro-β-erythroidine (DHβE) are potent and selective competitive inhibitors of 4β2 nicotinic acetylcholine receptors (nAChRs), but little is known about the molecular determinants of the sensitivity of this receptor subtype to inhibition by this class of antagonists. We addressed this issue by examining the effects of DHβE and a range of aromatic Erythrina alkaloids on [3H]cytisine binding and receptor function in conjunction with homo [...]
Constitutive Androstane Receptor-Mediated Up-Regulation of ATP-Driven Xenobiotic Efflux Transporters at the Blood-Brain Barrier [ARTICLES]
19/08/2010 00:03
ATP-driven efflux transporters at the blood-brain barrier both protect against neurotoxicants and limit drug delivery to the brain. In other barrier and excretory tissues, efflux transporter expression is regulated by certain ligand-activated nuclear receptors. Here we identified constitutive androstane receptor (CAR) as a positive regulator of P-glycoprotein, multidrug resistance-associated protein 2 (Mrp2), and breast cancer resistance protein (BCRP) expression in rat and mouse brain capillar [...]
19/08/2010 00:03
ATP-driven efflux transporters at the blood-brain barrier both protect against neurotoxicants and limit drug delivery to the brain. In other barrier and excretory tissues, efflux transporter expression is regulated by certain ligand-activated nuclear receptors. Here we identified constitutive androstane receptor (CAR) as a positive regulator of P-glycoprotein, multidrug resistance-associated protein 2 (Mrp2), and breast cancer resistance protein (BCRP) expression in rat and mouse brain capillar [...]
Inhibition of Histone Deacetylase 3 Produces Mitotic Defects Independent of Alterations in Histone H3 Lysine 9 Acetylation and Methylation [ARTICLES]
19/08/2010 00:03
The constitutive heterochromatin of the centromere is marked by high levels of trimethylated histone H3 lysine 9 (H3K9) and binding of the heterochromatin protein 1 (HP1), which are believed to also have an important role in mitosis. Histone deacetylase inhibitors (HDACis) are a class of anticancer agents that affect many cellular processes, including mitosis. Here we examine the mechanism by which these drugs disrupt mitosis. We have used Drosophila melanogaster embryos to demonstrate that tre [...]
19/08/2010 00:03
The constitutive heterochromatin of the centromere is marked by high levels of trimethylated histone H3 lysine 9 (H3K9) and binding of the heterochromatin protein 1 (HP1), which are believed to also have an important role in mitosis. Histone deacetylase inhibitors (HDACis) are a class of anticancer agents that affect many cellular processes, including mitosis. Here we examine the mechanism by which these drugs disrupt mitosis. We have used Drosophila melanogaster embryos to demonstrate that tre [...]
Evidence that Interaction between Conserved Residues in Transmembrane Helices 2, 3, and 7 Are Crucial for Human VPAC1 Receptor Activation [ARTICLES]
19/08/2010 00:03
The VPAC1 receptor belongs to family B of G protein-coupled receptors (GPCR-B) and is activated upon binding of the vasoactive intestinal peptide (VIP). Despite the recent determination of the structure of the N terminus of several members of this receptor family, little is known about the structure of the transmembrane (TM) region and about the molecular mechanisms leading to activation. In the present study, we designed a new structural model of the TM domain and combined it with experimental [...]
19/08/2010 00:03
The VPAC1 receptor belongs to family B of G protein-coupled receptors (GPCR-B) and is activated upon binding of the vasoactive intestinal peptide (VIP). Despite the recent determination of the structure of the N terminus of several members of this receptor family, little is known about the structure of the transmembrane (TM) region and about the molecular mechanisms leading to activation. In the present study, we designed a new structural model of the TM domain and combined it with experimental [...]
Novel Cationic Lipids with Enhanced Gene Delivery and Antimicrobial Activity [ARTICLES]
19/08/2010 00:03
Cationic lipids facilitate plasmid delivery, and some cationic sterol-based compounds have antimicrobial activity because of their amphiphilic character. These dual functions are relevant in the context of local ongoing infection during intrapulmonary gene transfer for cystic fibrosis. The transfection activities of two cationic lipids, dexamethasone spermine (DS) and disubstituted spermine (D2S), were tested as individual components and mixtures in bovine aortic endothelial cells and A549 cell [...]
19/08/2010 00:03
Cationic lipids facilitate plasmid delivery, and some cationic sterol-based compounds have antimicrobial activity because of their amphiphilic character. These dual functions are relevant in the context of local ongoing infection during intrapulmonary gene transfer for cystic fibrosis. The transfection activities of two cationic lipids, dexamethasone spermine (DS) and disubstituted spermine (D2S), were tested as individual components and mixtures in bovine aortic endothelial cells and A549 cell [...]
A Chemical Corrector Modifies the Channel Function of F508del-CFTR [ARTICLES]
19/08/2010 00:03
The deletion of Phe-508 (F508del) constitutes the most prevalent cystic fibrosis-causing mutation. This mutation leads to cystic fibrosis transmembrane conductance regulator (CFTR) misfolding and retention in the endoplasmic reticulum and altered channel activity in mammalian cells. This folding defect can however be partially overcome by growing cells expressing this mutant protein at low (27°C) temperature. Chemical "correctors" have been identified that are also effective in rescuing the [...]
19/08/2010 00:03
The deletion of Phe-508 (F508del) constitutes the most prevalent cystic fibrosis-causing mutation. This mutation leads to cystic fibrosis transmembrane conductance regulator (CFTR) misfolding and retention in the endoplasmic reticulum and altered channel activity in mammalian cells. This folding defect can however be partially overcome by growing cells expressing this mutant protein at low (27°C) temperature. Chemical "correctors" have been identified that are also effective in rescuing the [...]
Cellular and Pharmacological Selectivity of the Peroxisome Proliferator-Activated Receptor-{beta}/{delta} Antagonist GSK3787 [ARTICLES]
19/08/2010 00:03
The availability of high-affinity agonists for peroxisome proliferator-activated receptor-β/ (PPARβ/) has led to significant advances in our understanding of the functional role of PPARβ/. In this study, a new PPARβ/ antagonist, 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), was characterized using in vivo and in vitro models. Orally administered GSK3787 caused antagonism of 4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethy [...]
19/08/2010 00:03
The availability of high-affinity agonists for peroxisome proliferator-activated receptor-β/ (PPARβ/) has led to significant advances in our understanding of the functional role of PPARβ/. In this study, a new PPARβ/ antagonist, 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), was characterized using in vivo and in vitro models. Orally administered GSK3787 caused antagonism of 4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethy [...]
Arg13 of B-Type Natriuretic Peptide Reciprocally Modulates Binding to Guanylyl Cyclase but Not Clearance Receptors [ARTICLES]
19/08/2010 00:03
B-type natriuretic peptide (BNP) decreases cardiac preload and hypertrophy. As such, synthetic BNP, nesiritide, was approved for the treatment of acutely decompensated heart failure. However, two problems limit its therapeutic potential. First, ensuing hypertension decreases urine output, and second, guanylyl cyclase-A (GC-A), the primary signaling receptor for BNP, is down-regulated in heart failure. Thus, alternative or chimeric natriuretic peptides maintaining the renal but lacking the vasor [...]
19/08/2010 00:03
B-type natriuretic peptide (BNP) decreases cardiac preload and hypertrophy. As such, synthetic BNP, nesiritide, was approved for the treatment of acutely decompensated heart failure. However, two problems limit its therapeutic potential. First, ensuing hypertension decreases urine output, and second, guanylyl cyclase-A (GC-A), the primary signaling receptor for BNP, is down-regulated in heart failure. Thus, alternative or chimeric natriuretic peptides maintaining the renal but lacking the vasor [...]
The Histone Deacetylase Inhibitor MGCD0103 Has Both Deacetylase and Microtubule Inhibitory Activity [ARTICLES]
19/08/2010 00:03
Histone deacetylase inhibitors (HDACis) are currently in trial or are in clinical use for the treatment of a number of tumor types. The clinical efficacy of HDACis can be partly attributed to the modulation of the cell cycle by the HDACis. Here, we have examined the effects of N-(2-aminophenyl)-4-((4-pyridin-3-ylpyrimidin-2-ylamino)methyl)benzamide (MGCD0103), a class I-selective histone deacetylase inhibitor, on the cell cycle and cell killing. Surprisingly, MGCD0103 treatment failed to initia [...]
19/08/2010 00:03
Histone deacetylase inhibitors (HDACis) are currently in trial or are in clinical use for the treatment of a number of tumor types. The clinical efficacy of HDACis can be partly attributed to the modulation of the cell cycle by the HDACis. Here, we have examined the effects of N-(2-aminophenyl)-4-((4-pyridin-3-ylpyrimidin-2-ylamino)methyl)benzamide (MGCD0103), a class I-selective histone deacetylase inhibitor, on the cell cycle and cell killing. Surprisingly, MGCD0103 treatment failed to initia [...]
Delineating the Mode of Action of Adenosine A1 Receptor Allosteric Modulators [ARTICLES]
19/08/2010 00:03
Despite the identification of 2-amino-3-benzoylthiophenes (2A3BTs) as the first example of small-molecule allosteric potentiators of agonist function at a G protein-coupled receptor (GPCR)—the adenosine A1 receptor—their mechanism of action is still not fully understood. We now report the mechanistic basis for the complex behaviors noted for 2A3BTs at A1 receptors. Using a combination of membrane-based and intact-cell radioligand binding, multiple signaling assays, and a native tiss [...]
19/08/2010 00:03
Despite the identification of 2-amino-3-benzoylthiophenes (2A3BTs) as the first example of small-molecule allosteric potentiators of agonist function at a G protein-coupled receptor (GPCR)—the adenosine A1 receptor—their mechanism of action is still not fully understood. We now report the mechanistic basis for the complex behaviors noted for 2A3BTs at A1 receptors. Using a combination of membrane-based and intact-cell radioligand binding, multiple signaling assays, and a native tiss [...]
Allosteric Ligands of the Glucagon-Like Peptide 1 Receptor (GLP-1R) Differentially Modulate Endogenous and Exogenous Peptide Responses in a Pathway-Selective Manner: Implications for Drug Screening [ARTICLES]
19/08/2010 00:03
The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of insulin secretion and a major therapeutic target for treatment of diabetes. However, GLP-1 receptor function is complex, with multiple endogenous peptides that can interact with the receptor, including full-length (1–37) and truncated (7–37) forms of GLP-1 that can each exist in an amidated form and the related peptide oxyntomodulin. We have investigated two GLP-1 receptor allosteric modulators, Novo Nordisk compound [...]
19/08/2010 00:03
The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of insulin secretion and a major therapeutic target for treatment of diabetes. However, GLP-1 receptor function is complex, with multiple endogenous peptides that can interact with the receptor, including full-length (1–37) and truncated (7–37) forms of GLP-1 that can each exist in an amidated form and the related peptide oxyntomodulin. We have investigated two GLP-1 receptor allosteric modulators, Novo Nordisk compound [...]
Resveratrol Protects Dopamine Neurons Against Lipopolysaccharide-Induced Neurotoxicity through Its Anti-Inflammatory Actions [ARTICLES]
19/08/2010 00:03
Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by a progressive loss of dopamine (DA) neurons in the substantia nigra. Accumulating evidence indicates that inhibition of microglia-mediated neuroinflammation may become a reliable protective strategy for PD. Resveratrol, a nonflavonoid polyphenol naturally found in red wine and grapes, has been known to possess antioxidant, anticancer, and anti-inflammatory properties. Although recent studies have shown [...]
19/08/2010 00:03
Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by a progressive loss of dopamine (DA) neurons in the substantia nigra. Accumulating evidence indicates that inhibition of microglia-mediated neuroinflammation may become a reliable protective strategy for PD. Resveratrol, a nonflavonoid polyphenol naturally found in red wine and grapes, has been known to possess antioxidant, anticancer, and anti-inflammatory properties. Although recent studies have shown [...]
Protein Kinase C-{eta} and Phospholipase D2 Pathway Regulates Foam Cell Formation via Regulator of G Protein Signaling 2 [ARTICLES]
19/08/2010 00:03
Regulator of G protein signaling 2 (RGS2) is a GTPase-activating protein for Gq, which is involved in regulating various vascular functions. To understand how RGS2 regulates foam cell formation, the present study identified signaling pathways controlled by lipopolysaccharide (LPS) and discovered new mechanisms whereby protein kinase C (PKC)- and phospholipase D (PLD) 2 regulate RGS2 expression. The toll-like receptor (TLR) 4 agonist LPS caused foam cell formation of Raw264.7 macrophages and dra [...]
19/08/2010 00:03
Regulator of G protein signaling 2 (RGS2) is a GTPase-activating protein for Gq, which is involved in regulating various vascular functions. To understand how RGS2 regulates foam cell formation, the present study identified signaling pathways controlled by lipopolysaccharide (LPS) and discovered new mechanisms whereby protein kinase C (PKC)- and phospholipase D (PLD) 2 regulate RGS2 expression. The toll-like receptor (TLR) 4 agonist LPS caused foam cell formation of Raw264.7 macrophages and dra [...]
Antipsychotic Drugs Regulate Hedgehog Signaling by Modulation of 7-Dehydrocholesterol Reductase Levels [ARTICLES]
19/08/2010 00:03
Recently we identified GANT61, a small-molecule antagonist of Gli transcription factors, which are the final effectors of the mammalian Hedgehog (HH) signaling pathway. Here we describe a diamine substructure of GANT61 that carries the biological activity and show that this part of the molecule is structurally related to trans-1,4-bis(2-chlorobenzaminomethyl)cyclohexane dihydrochloride (AY9944), an inhibitor of the enzymatic activity and transcriptional inducer of 7-dehydrocholesterol-reductase [...]
19/08/2010 00:03
Recently we identified GANT61, a small-molecule antagonist of Gli transcription factors, which are the final effectors of the mammalian Hedgehog (HH) signaling pathway. Here we describe a diamine substructure of GANT61 that carries the biological activity and show that this part of the molecule is structurally related to trans-1,4-bis(2-chlorobenzaminomethyl)cyclohexane dihydrochloride (AY9944), an inhibitor of the enzymatic activity and transcriptional inducer of 7-dehydrocholesterol-reductase [...]
Efficient Hypoxic Activation of the Anticancer Agent AQ4N by CYP2S1 and CYP2W1 [ARTICLES]
19/08/2010 00:03
AQ4N [1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione], a prodrug with two dimethylamino N-oxide groups, is converted to the topoisomerase II inhibitor AQ4 [1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxy-anthracene-9,10-dione] by reduction of the N-oxides to dimethylamino substituents. Earlier studies showed that several drug-metabolizing cytochrome P450 (P450) enzymes can catalyze this reductive reaction under hypoxic conditions comparable with those in [...]
19/08/2010 00:03
AQ4N [1,4-bis{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione], a prodrug with two dimethylamino N-oxide groups, is converted to the topoisomerase II inhibitor AQ4 [1,4-bis{[2-(dimethylamino)ethyl]amino}-5,8-dihydroxy-anthracene-9,10-dione] by reduction of the N-oxides to dimethylamino substituents. Earlier studies showed that several drug-metabolizing cytochrome P450 (P450) enzymes can catalyze this reductive reaction under hypoxic conditions comparable with those in [...]
Regulation of Mouse Brain-Selective Sulfotransferase Sult4a1 by cAMP Response Element-Binding Protein and Activating Transcription Factor-2 [ARTICLES]
19/08/2010 00:03
Sulfotransferase 4A1 (SULT4A1) is a novel cytosolic sulfotransferase that is primarily expressed in the brain. To date, no significant enzyme activity or biological function for the protein has been identified, although it is highly conserved between species. Mutations in the SULT4A1 gene have been linked to schizophrenia susceptibility, and recently, its stability was shown to be regulated by Pin1, a peptidyl-prolyl cis-trans isomerase implicated in several neurodegenerative diseases. In this [...]
19/08/2010 00:03
Sulfotransferase 4A1 (SULT4A1) is a novel cytosolic sulfotransferase that is primarily expressed in the brain. To date, no significant enzyme activity or biological function for the protein has been identified, although it is highly conserved between species. Mutations in the SULT4A1 gene have been linked to schizophrenia susceptibility, and recently, its stability was shown to be regulated by Pin1, a peptidyl-prolyl cis-trans isomerase implicated in several neurodegenerative diseases. In this [...]
The Effect of Allosteric Modulators on the Kinetics of Agonist-G Protein-Coupled Receptor Interactions in Single Living Cells [ARTICLES]
19/08/2010 00:03
Allosteric binding sites on adenosine -A1 and -A3 receptors represent attractive therapeutic targets for amplifying, in a spatially and temporally selective manner, the tissue protective actions of endogenous adenosine. This study has directly quantified the kinetics of agonist/G protein-coupled receptor interactions at the single-cell level, reflecting the physiological situation in which intracellular signaling proteins can exert major allosteric effects on agonist-receptor interactions. The [...]
19/08/2010 00:03
Allosteric binding sites on adenosine -A1 and -A3 receptors represent attractive therapeutic targets for amplifying, in a spatially and temporally selective manner, the tissue protective actions of endogenous adenosine. This study has directly quantified the kinetics of agonist/G protein-coupled receptor interactions at the single-cell level, reflecting the physiological situation in which intracellular signaling proteins can exert major allosteric effects on agonist-receptor interactions. The [...]
Reversible, Allosteric Small-Molecule Inhibitors of Regulator of G Protein Signaling Proteins [ARTICLES]
19/08/2010 00:03
Regulators of G protein signaling (RGS) proteins are potent negative modulators of G protein signaling and have been proposed as potential targets for small-molecule inhibitor development. We report a high-throughput time-resolved fluorescence resonance energy transfer screen to identify inhibitors of RGS4 and describe the first reversible small-molecule inhibitors of an RGS protein. Two closely related compounds, typified by CCG-63802 [((2E)-2-(1,3-benzothiazol-2-yl)-3-[9-methyl-2-(3-methylphe [...]
19/08/2010 00:03
Regulators of G protein signaling (RGS) proteins are potent negative modulators of G protein signaling and have been proposed as potential targets for small-molecule inhibitor development. We report a high-throughput time-resolved fluorescence resonance energy transfer screen to identify inhibitors of RGS4 and describe the first reversible small-molecule inhibitors of an RGS protein. Two closely related compounds, typified by CCG-63802 [((2E)-2-(1,3-benzothiazol-2-yl)-3-[9-methyl-2-(3-methylphe [...]
Bryostatin 1 Inhibits Phorbol Ester-Induced Apoptosis in Prostate Cancer Cells by Differentially Modulating Protein Kinase C (PKC) {delta} Translocation and Preventing PKC{delta}-Mediated Release of Tumor Necrosis Factor-{alpha} [ARTICLES]
19/08/2010 00:03
Bryostatin 1, a macrocyclic lactone that has been widely characterized as an ultrapotent protein kinase C (PKC) activator, displays marked pharmacological differences with the typical phorbol ester tumor promoters. Bryostatin 1 impairs phorbol 12-myristate 13-acetate (PMA)-induced tumor promotion in mice and is in clinical trials as an anticancer agent for a number of hematopoietic malignancies and solid tumors. In this study, we characterized the effect of bryostatin 1 on LNCaP prostate cancer [...]
19/08/2010 00:03
Bryostatin 1, a macrocyclic lactone that has been widely characterized as an ultrapotent protein kinase C (PKC) activator, displays marked pharmacological differences with the typical phorbol ester tumor promoters. Bryostatin 1 impairs phorbol 12-myristate 13-acetate (PMA)-induced tumor promotion in mice and is in clinical trials as an anticancer agent for a number of hematopoietic malignancies and solid tumors. In this study, we characterized the effect of bryostatin 1 on LNCaP prostate cancer [...]
The Role of the Methionines and Histidines in the Transmembrane Domain of Mammalian Copper Transporter 1 in the Cellular Accumulation of Cisplatin [ARTICLES]
19/08/2010 00:03
Mammalian copper transporter 1 (CTR1) is a high-affinity copper influx transporter that also mediates the uptake of platinum-containing chemotherapeutic agents including cisplatin (cDDP). Methionines 150, 154, and histidine 139 have been proposed to form a series of stacked rings in the pore formed by the CTR1 homotrimer, each of which is required for maximal copper transport. To examine the mechanism by which hCTR1 also transports cDDP, variant forms of hCTR1 in which methionines 150 and 154 w [...]
19/08/2010 00:03
Mammalian copper transporter 1 (CTR1) is a high-affinity copper influx transporter that also mediates the uptake of platinum-containing chemotherapeutic agents including cisplatin (cDDP). Methionines 150, 154, and histidine 139 have been proposed to form a series of stacked rings in the pore formed by the CTR1 homotrimer, each of which is required for maximal copper transport. To examine the mechanism by which hCTR1 also transports cDDP, variant forms of hCTR1 in which methionines 150 and 154 w [...]