Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The glucocorticoid receptor is an intracellular protein which possesses three distinct domains, one that binds agonist and antagonist steroids, one that binds DNA, and one that binds anti-receptor antibodies and is required for glucocorticoid modulation of gene expression. In intact cells, receptor number, affinity and activity can change in response to factors that bind to the receptor, or that act indirectly through ill-defined mechanisms which may include resumption or arrest of cell cycling and variations in intracellular calcium ion concentrations. Some of these factors appear to exert their effect by controlling critical receptor properties such as ATP-dependent phosphorylation, integrity of thiol groups, and exposure of key amino acid residues. Glucocorticoid agonists promote the 'transformation' of the receptor into the DNA-binding state, which is competent for modulating gene expression. Glucocorticoid antagonists are steroids that interact with the receptor but either fail to produce a stable complex or produce a stable but inefficient complex. Although substituent groups that confer agonist or antagonist activity to the steroid have been identified, the molecular determinants of this difference at the receptor level remain unknown. Most in vitro and in vivo data on receptor regulation can be accommodated by postulating the existence of an intracellular cycle that involves five states of the receptor. The active free receptor is phosphorylated, reduced, and presumably oligomeric (state A). Following binding of an agonist (state B), it can become transformed by dissociation into its subunits and dephosphorylation (state C). The transformed receptor then interacts with chromatin (state D). Dissociation of the steroid and oxidation of receptor thiol group(s) lead to the inactive receptor form (state E). Reduction and rephosphorylation of the receptor enable it to bind steroids again so that the cycle is closed.
Mol Cell Endocrinol 1984 Nov
PMID:Structure and regulation of the glucocorticoid hormone receptor. 639 7

Steady-state velocity studies using a substrate regenerating system showed that efrapeptin, citreoviridin and aurovertin inhibit both membrane-bound and soluble mitochondrial ATPase (coupling factor F1) from Trypanosoma cruzi. Maximal inhibitions of ATP hydrolysis produced by efrapeptin and citreoviridin were 100-93%, while the maximal inhibition produced by aurovertin was 40%. Half-maximal inhibitory concentrations decreased in the order citreoviridin greater than aurovertin greater than efrapeptin. Dissociation constants (KD) for the inhibitor-F1 complex were 81 nM (efrapeptin), 6.6 muM (aurovertin) and 40 muM (citreoviridin); KD values for the membrane-bound F1 were 2-4 fold higher than for soluble F1. Representation of efrapeptin inhibition data in the Hill form yielded straight lines (n = 1) while the same representation of citreoviridin inhibition yielded concave down plots. In contrast to the immediate effect of citreoviridin and aurovertin, efrapeptin inhibition was time-dependent. The onset of inhibition, which was pseudo-first-order with respect to efrapeptin, indicated that ATP may promote the binding of efrapeptin to the enzyme. The kinetics of ATP hydrolysis by T. cruzi ATPase as a function MgATP concentration could be explained by the presence of two substrate sites on the enzyme, interacting in such a way that the binding and catalytic events at one site were conformationally linked to the events at the other site, as with the mammalian ATPase. When the antibiotics were assayed at increasing substrate concentrations, efrapeptin produced a linear, mixed-type inhibition whereas citreoviridin produced a parabolic noncompetitive-type inhibition. The aurovertin effect was unusual since the extent of inhibition was greater at high substrate concentrations. Maximal concentrations of all the assayed antibiotics linearized the biphasic double reciprocal plot of control ATPase activity. Comparison of T. cruzi and mammalian F1 responses to the assayed antibiotics revealed the operation of similar inhibition mechanisms but the T. cruzi enzyme was significantly less sensitive to inhibitors than its mammalian counterpart.
Mol Biochem Parasitol 1981 Jul
PMID:Influence of efrapeptin, aurovertin and citreoviridin on the mitochondrial adenosine triphosphatase from Trypanosoma cruzi. 645 45

We have studied the reversible dissociation of core size DNA from chicken erythrocyte nucleosome core particles in solutions containing 0 X 1 M to 0 X 6 M-NaCl. Dissociation increases with increasing NaCl concentration, increasing temperature and decreasing particle concentration. At high particle concentrations, no free DNA is observed below 0 X 3 M-NaCl, whereas above 0 X 3 M-NaCl a lower limit of dissociation is reached. A theoretical analysis based on the migrating-octamer mechanism of Stein is in disagreement with his conclusions concerning dependence of core particle dissociation on particle concentration, but provides a good explanation for our observations, and those of others, using salt concentrations up to 1 M-NaCl. It appears that the core particle is not stabilized primarily by electrostatic interactions. DNA length is not critical for core particle stabilization. The conformation of remaining intact nucleosome core particles changes only moderately within the range of NaCl concentrations studied. Crosslinking by copper phenanthroline of the Cys110 histone H3 single sulfhydryl groups in the intact nucleosome core particle leads to a decrease in stability, yet essentially unchanged hydrodynamic properties are maintained at 0 X 6 M-NaCl, confirming conclusions derived from the behavior of the native core particles. Values for density increments of nucleosome core particles over a range of NaCl concentrations are also given. A method is described for studying binding of histones to nucleosome core particles in the ultracentrifuge by scanning at 230 and 260 nm.
J Mol Biol 1984 Jun 15
PMID:Nucleosome core particle stability and conformational change. Effect of temperature, particle and NaCl concentrations, and crosslinking of histone H3 sulfhydryl groups. 673 80

Halobacterium halobium has right-handed helical flagella. During the logarithmic phase of growth, cells are predominantly monopolar, whereas in the stationary phase they are mostly bipolarly flagellated. The flagellar bundle consists of several filaments. Halobacteria swim forward by clockwise and backwards by counterclockwise rotation of their flagella. The flagellar bundle does not fly apart when the sense of rotation changes. In addition to the flagella attached to the cells, large amounts of loose flagella, which aggregate into thick super-flagella, can be observed at all phases of growth. During stationary phase, the production of these super-flagella, which are generally 10 to 20 times longer than the cell body, is significantly higher. Dissociation and association by high temperature and differential centrifugation allow the isolation of pure flagella. Three different protein bands, of 23,500, 26,500 and 31,500 apparent molecular weights, are seen on sodium dodecyl sulphate/polyacrylamide gels. Antibodies against halobacterial flagella were produced in chicken; these antibodies interact with the flagella even in 4 M-NaCl. Rotation of tethered cells demonstrates that Halobacteria move due to the rotation of the flagella.
J Mol Biol 1984 Jul 15
PMID:Morphology, function and isolation of halobacterial flagella. 674 81

Surface membrane immunoglobulin from MOPC-315 plasmacytoma cells (smM315) was isolated by nonionic detergent lysis of radioiodinated cells and affinity chromatography on Dnp-aminohexyl-Sepharose 4B. Verification of the solubilized molecule as an integral membrane protein, distinct from secreted MOPC-315 IgA (M315) was accomplished by NaDodSO4-PAGE, charge-shift electrophoresis and molecular sieve gel filtration with NP-40 and deoxycholate. smM315 was compared to reduced and alkylated monomeric secreted immunoglobulins from MOPC-315, MOPC-460, and XRPC-25 by quantitative affinity chromatography (QAC) using two differently substituted Dnp-aminohexyl-Sepharose 4B resins. Unique patterns of cross-reactivity of all secreted myeloma proteins were independently established with a competitive hapten inhibition assay using 125I-Dnp26BSA as the precipitating probe. After derivation with dinitrobenzylsulfonate, Dnp-aminohexyl-Sepharose 4B was modified with succinic anhydride which, with the inclusion of 0.03% Doc in a PBS and 0.1% NP-40 buffer, prevented nonhapten specific protein-matrix interactions during QAC. Dissociation constants determined by QAC for three ligands, (dinitrophenyl-glycine, trinitrophenyl-amino-caproate and tetramethylrhodamine) were essentially the same for smM315 and M315. Both of the other nitrophenyl binding IgA myelomas had distinct and significant differences in dissociation constants. Thus, for a differentiated antibody secreting cell which has undergone a heavy chain class switch, such as MOPC-315, the cell surface immunoglobulin has an identical ligand binding active-site as the secreted immunoglobulin.
Mol Immunol 1983 Jan
PMID:Determination of dissociation constants and ligand specificity of detergent solubilized surface membrane immunoglobulin A from MOPC-315. 685 76

The flavoprotein NADPH-adrenodoxin reductase and the iron sulfur protein adrenodoxin function as a short electron transport chain which donates electrons one-at-a-time to adrenal cortex mitochondrial cytochromes P-450. The soluble adrenodoxin acts as a mobile one-electron shuttle, forming a complex first with NADPH-reduced adrenodoxin reductase from which it accepts an electron, then dissociating, and finally reassociating with and donating an electron to the membrane-bound cytochrome P-450 (Fig. 9). Dissociation and reassociation with flavoprotein then allows a second cycle of electron transfers. A complex set of factors govern the sequential protein-protein interactions which comprise this adrenodoxin shuttle mechanism; among these factors, reduction of the iron sulfur center by the flavin weakens the adrenodoxin-adrenodoxin reductase interaction, thus promoting dissociation of this complex to yield free reduced adrenodoxin. Substrate (cholesterol) binding to cytochrome P-450scc both promotes the binding of the free adrenodoxin to the cytochrome, and alters the oxidation-reduction potential of the heme so as to favor reduction by adrenodoxin. The cholesterol binding site on cytochrome P-450scc appears to be in direct communication with the hydrophobic phospholipid milieu in which this substrate is dissolved. Specific effects of both phospholipid headgroups and fatty acyl side-chains regulate the interaction of cholesterol with its binding side. Cardiolipin is an extremely potent positive effector for cholesterol binding, and evidence supports the existence of a specific effector lipid binding site on cytochrome P.450scc to which this phospholipid binds.
Mol Cell Biochem 1982 May 28
PMID:Steroidogenic electron transport in adrenal cortex mitochondria. 705 Jun 53

Binding of CO to the hemoglobin of Tunnus thynnus has been studied by kinetic and static methods in the range pH 6.75-8.0 and at temperatures between 1.5-40 degrees C. The results may be described in terms of the two-state model of cooperativity (Monod. J., Wyman, J., and Changeux, J. P. (1965) J. Mol. Biol. 12, 88-118) extended to include chain differences. The rate constants for CO binding to alpha and beta chains in the R state, at 20 degrees C, were 8.4 and 1.9 microM-1 s-1 with associated apparent activation energies of 3.5 and 10.5 kcal mol-1. Dissociation from the R state was monophasic with a rate constant, at 20 degrees C, of 0.016 s-1 and Ea of 26.4 kcal mol-1. The difference spectrum for binding of CO to the alpha chain in the T state is displaced 2 nm to the red as compared to the spectra associated with CO binding to the beta chain in the T state and to both chains in the R state. The proportion of T state hemoglobin present at different fractional saturations can thus be measured and compared with the results predicted from the model. When the temperature is raised, the value of L decreases greatly with an enthalpy of +80 kcal mol-1. The effects of the change in L override the decrease in intrinsic CO affinity of T. thynnus hemoglobin in the R and T states and result in a reverse temperature dependence of CO equilibria compared to mammalian hemoglobins.
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PMID:Cooperative ligand binding to hemoglobin. Effects of temperature and pH on a hemoglobin with spectrophotometrically distinct chains (Tunnus thynnus). 706 66

Evaluation of TSH binding to plasma membranes of porcine thyroid revealed unique sensitivity to pH and temperature. Analysis of apparent equilibrium binding yielded a linear Scatchard plot at the optimal pH of 6.0, indicating one class of binding sites. At physiological pH 7.4 a curvilinear Scatchard plot was obtained, resolved by computer analysis into two classes of binding sites of different affinities and capacities. Treatment of membranes with phospholipase C resulted in a 20% decrease in the number of high affinity sites, but no change occurred in binding affinity. In contrast, low affinity sites were not altered. To evaluate the significance of the curvilinear Scatchard plot, the kinetics of association were examined. The intrinsic Kd (kd/ka) was 0.20 nM, a value essentially equivalent to that of the high affinity binding component. The 'negative cooperativity' model of hormone binding was evaluated by examining the effect of excess unlabeled TSH on dissociation rate. Dissociation of bound 125I-labeled TSH was biphasic, and was enhanced by unlabeled hormone, regardless of whether the membranes were prelabeled at pH 6.0 or 7.4. This effect was not correlated with curvilinear Scatchard plots, and therefore not proof of negative cooperativity. Binding sites for TSH were further distinguished by their sensitivity to temperature. A van't Hoff plot of temperature dependence of the apparent Kd of the high affinity site was linear from 4 to 37 degrees C. In contrast, the apparent Kd of low affinity binding did not vary with respect to temperature. These results demonstrate that there are at least two independent binding sites for TSH on porcine thyroid plasma membranes, distinguishable by their equilibrium binding properties.
Mol Cell Endocrinol
PMID:Thyrotropin binding to porcine thyroid plasma membranes: kinetic and thermodynamic analyses. 715 94

The structural transitions of the tetrameric rabbit muscle pyruvate kinase induced by guanidine hydrochloride and urea are characterized by elastic and quasi-elastic light-scattering, sedimentation velocity, and intrinsic viscosity experiments as well as by protein fluorescence, circular dichroism, and enzymic activity measurements. The transition curves are shown to be reversible. We find a new pathway of unfolding which is different from that described in the literature: The first intermediate with increasing concentration of denaturant is a less compact and inactive tetramer which can be renatured if substrates are added. Dissociation of the tetramer results in an expanded dimer with a partial loss of the secondary structure. The final state is a completely disordered monomer. These intermediates are consistent with a domain structure of pyruvate kinase, as it was suggested by Stammers & Muirhead [Stammers, D. K., & Muirhead, H. (1975) J. Mol. Biol. 95, 213--225] on the basis of their X-ray data. Using Schellman's solvent denaturation model [Schellman, J. A. (1978) Biopolymers 17, 1305--1322], we calculate the free energies of stabilization of the folding--unfolding equilibrium.
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PMID:Reversible solvent denaturation of rabbit muscle pyruvate kinase. 721 11

Cock brain coated vesicles (CBCVs) were purified and compared with porcine brain coated vesicles (PBCVs) from several biochemical aspects. Clathrin heavy and light chains of CBCVs were immunologically similar to those of PBCVs. Coat proteins (CPs) of CBCVs behaved in almost the same manner as those of PBCVs for limited proteolysis. Dissociation of CPs from CBCVs by treatment with 10 mM Tris-Cl, pH 8.5, or 2M urea resembled that of CPs from PBCVs. pH dependency of dissociation of CPs from CBCVs was slightly different from those of PBCVs.
Comp Biochem Physiol B Biochem Mol Biol 1995 Feb
PMID:Comparative biochemical study of coated vesicles purified from cock brains. 753 6


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