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PubMed1975

Subunit interactions in aspartate transcarbamylase. The interaction between catalytic and regulatory subunits and the effect of ligands.

The interaction between the catalytic subunit (c3) and the regulatory subunit (r2) of aspartate transcarbamylase from Escherichia coli was studied by measuring the reversible formation of the c3r6 complex as a function of r2 concentration. Conversion to the native enzyme was prevented by using a very low concentration of c2 (40 ng per ml) in the presence of bovine serum albumin. A simple hyperbolic r2 saturation curve was obtained suggesting the presence of only one kind of c:r domain. From the association constant for the formation of c3r6, the free energy of c:r interaction can be estimated to be about -10 Cal per mole. Neither CTP nor ATP appears to affect the strength of c:r interaction in this complex. Succinate in the presence of carbamyl phosphate promotes tighter binding. At higher concentration of c3 and nonsaturating levels of r2, conversion to the native enzyme (c3r6) takes place. This renaturation process is second order with respect to the concentration of c3 and is virtually irreversible. Renaturation is inhibited by saturating levels of r2 and to some extent by both CTP and ATP. The effect of ligands on c:r interactions reported here may have significance in the allosteric mechanism of the native enzyme.

Adenosine Triphosphate↗
PubMed1992

[Experimentally-induced stress in dyadic interactions. Presentation of the EISI (experimentally-induced stress in dyadic interactions) experiment].

In this article we present an experimental study (EISI-experiment: experimental induced stress in dyadic interaction), which focuses on a method for analysing individual and dyadic stress-experience and coping as well as its influence on dyadic interaction. The experiment offers a new diagnostic approach to analyse interaction processes under stress. We report the concept of our experimental design and show some first results. The findings suggest that our method is useful for the examination of stress phenomena in close relationships. It allows the investigation of interactional processes and in this context especially of "dyadic coping", a form of stress-management by couples.

Adaptation, Psychological↗
PubMed2005

[Interaction between balofloxacin and DNA and the influence of Mg2+ on the interaction].

AIM: To study the binding mode of balofloxacin with DNA and evaluate the influence of Mg2+ on the binding between balofloxacin and DNA. METHODS: Fluorescent spectroscopy was used to study the interaction of balofloxacin with DNA and to calculate the thermodynamic constants. UV-Vis spectra, DNA viscosity titration, competition experiment and the effect of dsDNA and ssDNA on the fluorescense intensity were used to identify the binding mode. RESULTS: Balofloxacin interacted with CT-DNA with a quenching constant of (5.43 +/- 0.07) x 10(3) L x mol(-1). The interaction was exothermic with a Van't Hoff enthalply of - 8.03 kJ x mol(-1) x Mg2+ cation could enhance the quenching constant between balofloxacin and DNA. CONCLUSION: Balofloxacin interacted with CT-DNA in the mode of groove binding and Mg2+ could mediate the binding of balofloxacin to DNA.

Animals↗
PubMed1978

Interaction of metal ions with nucleic acids. Interaction of copper(II) with adenosine and its derivatives.

The interaction of copper(II) with adenosine, 2'-deoxyadenosine, 1-methyladenosine, 7-deazaadenosine and AMP was studied by spectroscopic and magnetochemical methods. In non-aqueous medium, copper(II) interacts with adenosine and AMP at N-7 and N-1, and with 1-methyladenosine at N-7 and N-3. The copper ion is not bound to the NH2 group. In aqueous solution, copper(II) interacts both with N-7 and N-1 of adenosine, and in AMP additionally with the phosphate group. The interaction of copper(II) with the heterocyclic part, but not withthe phosphate group, is dependent on the extent of protonation of the molecular. A crystalline AMP-copper(II) complex [Cu(C10H12N5O7P).(H2O)2] was obtained; the phosphate group and probably N-7 are involved in the complex formation.

Adenosine↗
PubMed1983

In vitro analysis of allogeneic lymphocyte interaction. VI. I-J-restricted self-reactive and alloreactive components of allogeneic effect factor (AEF) are distinct I-J- molecules that interact with I-J+ T cells and antigen-presenting cells.

An allogeneic effect factor (AEF) generated across an I-J incompatibility was derived from MLR cultures of alloactivated B10.A(3R) responder T cells and irradiated T cell-depleted B10.A(5R) stimulator spleen cells. This AEF consists of two soluble, secreted I-J-restricted helper components. One helper component, TH-I, recognizes self-I-J determinants on an I-J+ B10.A(3R) antigen-presenting cell (APC), whereas the other helper component, TH-II, recognizes allo-I-J determinants on an I-J+ B10.A(5R) APC. TH-I-B10.A(3R) APC interaction and TH-II-B10.A(5R) APC interaction each induce an in vitro primary anti-SRBC PFC response of either B10.A(3R) or B10.A(5R) B cells. Thus, I-J determinants serve as restricting elements during a TH-APC and not an APC-B interaction. TH-II mediates the I-J-restricted allogeneic effect required to activate T suppressor (TS) cells during a contact sensitivity or delayed-type hypersensitivity response to hapten-conjugated syngeneic lymphoid cells. This indicates that TH-II is also involved in a TH-pre-TS type interaction. TH-I and TH-II are I-J-, 68,000 m.w. molecules that differ by about 0.10 units in their pl values. Their charge difference is not due to an altered amount of sialylation or phosphorylation, but may result either from another form of altered glycosylation and/or from a difference in their primary structure. Peptide mapping analyses reveal that TH-I and TH-II possess at least 80% shared peptides and may be structurally homologous but nonidentical molecules; however, the possibility that TH-I and TH-II are structurally identical cannot be eliminated. Papain cleaves TH-I and TH-II into a 40,000 m.w. fragment. No subunit structure of TH-I and TH-II is apparent. It is suggested that TH-I and TH-II are I-J- -activated responder T cell-derived receptors for self-I-J and allo-I-J determinants, respectively.

Amino Acid Sequence↗
PubMed1994

Protein interactions in genetic recombination in Escherichia coli. Interactions involving RecO and RecR overcome the inhibition of RecA by single-stranded DNA-binding protein.

RecA promotes homologous pairing of single-stranded DNA (ssDNA) with double-stranded DNA (dsDNA). This reaction occurs inefficiently if the ssDNA substrate is preincubated with Escherichia coli ssDNA-binding protein (SSB). However, RecO and RecR can act together as accessory factors for RecA to overcome this inhibition by SSB (Umezu, K., Chi, N.-W., and Kolodner, R. D. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 3875-3879). To elucidate the mechanism that underlies this process, we examined protein-protein interactions between RecA, RecF, RecO, RecR, and SSB, and characterized the structure and activity of the ssDNA complexes formed with different combinations of these proteins. We obtained the following results. (i) RecO physically interacts with both RecR and SSB. The interaction between RecO and SSB is stronger than the RecO-RecR interaction. (ii) RecO and RecR do not remove SSB from SSB.ssDNA complexes, but instead bind to these complexes. The resulting RecO.RecR.SSB.ssDNA complexes were more active in RecA-mediated joint molecule formation than were SSB.ssDNA complexes. (iii) RecA can nucleate on the RecO.RecR.SSB.ssDNA complexes more efficiently than on SSB.ssDNA complexes. (iv) When RecA presynaptic filaments were formed in the presence of SSB, RecO, and RecR, the protein-DNA complexes obtained contained 70% of the amount of RecA required to saturate ssDNA. These complexes, however, can mediate joint molecule formation and strand exchange as efficiently as presynaptic filaments which are fully saturated with RecA. Based on these results, we propose dual roles for RecO and RecR in joint molecule formation. First, RecO and RecR bind to SSB.ssDNA complexes and modify their structure to allow RecA to nucleate on them efficiently. Second, RecO and RecR are retained in RecA presynaptic filaments and play a role in the subsequent homologous pairing process promoted by RecA.

Bacterial Proteins↗
PubMed1993

Structural determinants outside of the leucine zipper influence the interactions of CREB and ATF-2: interaction of CREB with ATF-2 blocks E1a-ATF-2 complex formation.

Dimerization of leucine zipper-containing proteins has been associated characteristically with the formation of a coiled-coil structure between two compatible leucine zipper motifs. In the present study we demonstrate the association of the leucine zipper of cAMP response element-binding protein (CREB) with a zinc finger motif of ATF-2. The association of the CREB leucine zipper with the ATF-2 zinc finger is stabilized if the ATF-2 leucine zipper is intact, implying that the preferred interactive structure of ATF-2 juxtaposes the amino-terminal zinc finger motif of this protein with the carboxy-terminal leucine zipper of this same protein. Furthermore, we demonstrate that the association of the CREB leucine zipper with the ATF-2 zinc finger in vitro blocks the association of the adenoviral E1a protein with ATF-2. Similarly, overexpression of full-length CREB, or a truncated version of this protein corresponding to the carboxy-terminal 74 amino acids that make up the DNA-binding and dimerization domains, can block the ATF-2-mediated transcriptional stimulation by E1a in vivo. Mutation of the ATF-2 zinc finger motif stimulates DNA binding of this protein, and abolishes interactions with E1a and CREB proteins. These results demonstrate that the structural conformation of ATF-2 is critical for DNA binding and protein-protein interactions and, further, that leucine zippers can mediate protein-protein interactions with structural motifs other than leucine zippers.

Activating Transcription Factors↗
PubMed1997

Phosphorylation of the synaptic protein interaction site on N-type calcium channels inhibits interactions with SNARE proteins.

The synaptic protein interaction (synprint) site on the N-type calcium channel alpha1B subunit binds to the soluble N-ethylmaleimide-sensitive attachment factor receptor (SNARE) proteins syntaxin and synaptosomal protein of 25 kDa (SNAP-25), and this association may be required for efficient fast synaptic transmission. Protein kinase C (PKC) and calcium and calmodulin-dependent protein kinase type II (CaM KII) phosphorylated a recombinant his-tagged synprint site polypeptide rapidly to a stoichiometry of 3-4 mol of phosphate/mol, whereas cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) phosphorylated the synprint peptide more slowly to a stoichiometry of <1 mol/mol. Two-dimensional phosphopeptide mapping revealed similar patterns of phosphorylation of synprint polypeptides and native rat brain N-type calcium channel alpha1B subunits by PKC and Cam KII. Phosphorylation of the synprint peptide with PKC or CaM KII, but not PKA or PKG, strongly inhibited binding of recombinant syntaxin or SNAP-25, even at a level of free calcium (15 microM) that stimulates maximal binding. In contrast, phosphorylation of syntaxin and SNAP-25 with PKC and CaM KII did not affect interactions with the synprint site. Binding assays with polypeptides representing the N- and C-terminal halves of the synprint site indicate that the PKC- and CaM KII-mediated inhibition of binding involves multiple, disperse phosphorylation sites. PKC or CaM KII phosphorylation of the synprint peptide also inhibited its interactions with native rat brain SNARE complexes containing syntaxin and SNAP-25. These results suggest that phosphorylation of the synprint site by PKC or CaM KII may serve as a biochemical switch for interactions between N-type calcium channels and SNARE protein complexes.

Animals↗
PubMed2005

P-glycoprotein interaction with risperidone and 9-OH-risperidone studied in vitro, in knock-out mice and in drug-drug interaction experiments.

The drug transporter P-glycoprotein (P-gp) influences drug distribution across the blood-brain barrier (BBB) by actively extruding drugs into the neural capillaries. Several psychotropic drugs, including nortriptyline (NT) and risperidone (Risp), are substrates of P-gp. Here we compared the in vitro P-gp interactions of Risp and its major metabolite, 9-OH-Risperidone (OH-Risp), with their distribution over the BBB in P-gp knock-out mice and in rats where P-gp was inhibited. K(m) and V(max) were determined by an in vitro ATPase assay, and V(max)/K(m) ratios of 2.7 and 0.5 were recorded for Risp and OH-Risp, respectively, suggesting that Risp is a better substrate for P-gp than OH-Risp. In Mdr1a (-/-) knock-out mice, the brain-serum ratios of both Risp and OH-Risp were more than ten times those of control mice (14 and 11, respectively). When P-gp was inhibited with cyclosporine A (CsA) in Wistar rats, the effect was an order of magnitude less than that observed for the knock-out mice experiments (1-1.5 times the controls), and co-administration of NT had no effect. In conclusion, both Risp and OH-Risp interact with P-gp in vitro, and P-gp has a profound effect on Risp and OH-Risp distribution over the BBB, as is evident from the knock-out mice experiments. Drug-drug interaction effects in relation to P-gp, however, appear to be more limited.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1987

Comparison of the molecular mass dependency of heparin stimulation of heparin cofactor II:thrombin interaction to antithrombin III:thrombin interaction.

The influence of increasing concentrations of heparin of different molecular mass (Mr) has been compared in potentiation of the rate of heparin cofactor II:thrombin interaction and of antithrombin III:thrombin interaction. Unfractionated and fractionated heparin showed a concentration dependent ascending and descending limb of stimulation of the rate for both inhibitors. Unfractionated heparin and fractions of 16.5 KDa or less showed a peak acceleration of the rate of interaction of thrombin with both inhibitors at 0.3 X 10(-6) M heparin although the observed maximum rate at this peak decreased with fall in Mr. For both inhibitors two high Mr fractions showed peak stimulation at a lower heparin concentration (0.3 X 10(-7) M) and approximately two-fold greater increase in rate than that observed with unfractionated heparin. Potentiation of heparin cofactor II inhibitory activity differed from that of antithrombin III in that it was reversed by lower ionic strength and was not reversed by a heparin pentasaccharide with high affinity for antithrombin III. It is proposed that differences in the profiles of stimulation by high Mr fractions to those of lower Mr are related to higher binding affinities for the inhibitor permitting maximal binding of heparin before the descending part of the slope due to saturation of thrombin (according to the template hypothesis).

Antithrombin III↗
PubMed2005

The Rab-interacting lysosomal protein, a Rab7 and Rab34 effector, is capable of self-interaction.

Rab-interacting lysosomal protein (RILP) has been identified as an interacting partner of the small GTPases Rab7 and Rab34. Active Rab7 recruits RILP on the late endosomal/lysosomal membrane and RILP then functions as a Rab7 effector controlling transport to degradative compartments. Indeed, RILP induces recruitment of dynein-dynactin motor complexes to Rab7-containing late endosomes and lysosomes. Recently, Rab7 and RILP have been found to be key proteins also for the biogenesis of phagolysosomes. Therefore, RILP represents probably an important factor for all endocytic routes to lysosomes. In this study, we show, using the yeast two-hybrid system, that RILP is able to interact with itself. The data obtained with the two-hybrid system were confirmed using co-immunoprecipitation in HeLa cells. The data together indicate that RILP, as already demonstrated for several other Rab effector proteins, is capable of self-association, thus probably forming a homo-dimer.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Deuterium isotope effects on hydrophobic interactions: the importance of dispersion interactions in the hydrophobic phase.

Hydrogen/deuterium isotope effects on hydrophobic binding were examined by means of reversed-phase chromatographic separation of protiated and deuterated isotopologue pairs for a set of 10 nonpolar and low-polarity compounds with 10 stationary phases having alkyl and aryl groups bonded to the silica surface. It was found that protiated compounds bind to nonpolar moieties attached to silica more strongly than deuterated ones, demonstrating that the CH/CD bonds of the solutes are weakened or have less restricted motions when bound in the stationary phase compared with the aqueous solvent (mobile phase). The interactions responsible for binding have been further characterized by studies of the effects of changes in mobile phase composition, temperature dependence of binding, and QSRR (quantitative structure-chromatographic retention relationship) analysis, demonstrating the importance of enthalpic effects in binding and differentiation between the isotopologues. To explain our results showing the active role of the hydrophobic (stationary) phase we propose a plausible model that includes specific contributions from aromatic edge-to-face attractive interactions and attractive interactions of aliphatic groups with the pi clouds of aromatic groups present as the solute or in the stationary phase.

Chromatography, High Pressure Liquid↗
PubMed2004

Conformationally constrained analogues of diacylglycerol (DAG). 23. Hydrophobic ligand-protein interactions versus ligand-lipid interactions of DAG-lactones with protein kinase C (PK-C).

The constrained glycerol backbone of DAG-lactones, when combined with highly branched alkyl chains, has engendered a series of DAG-lactone ligands capable of binding protein kinase C (PK-C) with affinities that approximate those of phorbol esters. These branched chains not only appear to be involved in making important hydrophobic contacts with the protein (specific interactions) but also provide adequate lipophilicity to facilitate partitioning into the lipid-rich membrane environment (nonspecific interactions). With the idea of minimizing the nonspecific interactions without reducing lipophilicity, the present work explores the strategy of relocating lipophilicity from the side chain to the lactone "core". Such a transfer of lipophilicity, exemplified by compounds 1 and 3, was conceived to allow the new hydrophobic groups on the lactone to engage in specific hydrophobic contacts inside the binding pocket without any expectation of interfering with the hydrogen-bonding network of the DAG-lactone pharmacophore. Surprisingly, both (E)-3 and (Z)-3 showed a significant decrease in binding affinity. From the molecular docking studies performed with the new ligands, we conclude that the binding pocket of the C1 domain of PK-C is sterically restricted and prevents the methyl groups at the C-3 position of the lactone from engaging in productive hydrophobic contacts with the receptor.

Binding Sites↗
PubMed2004

Interaction of Ferredoxin-NADP(+) Reductase with its Substrates: Optimal Interaction for Efficient Electron Transfer.

Electron transfer (ET) reactions in systems involving proteins require an oriented interaction between electron donor and acceptor in order to accommodate their respective redox centres in optimal orientation for efficient ET. Such type of reactions are critical for the maintenance of the physiological functions of living organisms, since they are implicated in vital actions, as is, for example, in the photosynthetic ET chain that leads to NADPH reduction. In this particular case, a small redox protein ET chain is responsible for ET from Photosystem I (PS I) to NADP(+). In this system the enzyme responsible for NADP(+) reduction is ferredoxin-NADP(+) reductase (FNR), a FAD-containing NADP(+) dependent reductase. In order to produce such reduction, this enzyme receives electrons from a [2Fe-2S] plant-type ferredoxin (Fd), which is previously reduced by PS I. Moreover, in the case of some algae and cyanobacteria, an FMN-dependent protein, flavodoxin (Fld), has been shown to replace Fd in this function. The processes of interaction and ET between FNR and all of its substrates involved in the photosynthetic ET chain, namely Fd, Fld and NADP(+)/H have been extensively investigated in recent years using a large number of techniques, including the introduction of site-specific mutations in combination with kinetic and structural studies of the produced mutants. The present manuscript summarises the information so far reported for an efficient interaction between FNR and its substrates, compares such information with that revealed by other systems for which the FNR structure is a prototype and, finally, discusses the implications of the processes of association in ET between FNR and its substrates.

FNR↗
PubMed2004

Analysis of two CBP (cAMP-response-element-binding protein-binding protein) interacting sites in GRIP1 (glucocorticoid-receptor-interacting protein), and their importance for the function of GRIP1.

The p160 co-activators, SRC1 (steroid receptor co-activator 1), GRIP1 (glucocorticoid-receptor-interacting protein 1) and ACTR (activator for thyroid hormone and retinoid receptors), have two ADs (activation domains), AD1 and AD2. AD1 is a binding site for the related co-activators, CBP (cAMP-response-element-binding protein-binding protein) and p300, whereas AD2 binds to another co-activator, co-activator-associated arginine methyltransferase 1 (CARM1). Here, we identified two CBP-interacting sites [amino acids 1075-1083 (site I) and 1095-1106 (site II)] in a so-called CBP-dependent transactivation domain (AD1; amino acids 1057-1109) of GRIP1. Site I was the major site for CBP-dependent AD1 transactivation activity of GRIP1 whereas, following the deletion of site II, full or partial transactivation activity was retained without the recruitment of CBP in yeast, HeLa, human embryonic kidney 293 and CV-1 cells. GRIP1 (with a deletion of site II) expressed stronger co-activator activity than that of wild-type GRIP1 in the TR (thyroid receptor) and the AR (androgen receptor), but not the ER (oestrogen receptor), systems in HeLa cells. We also demonstrated that these CBP-binding sites of GRIP1 are not the only functional domains for its AD1 function in TR, AR and ER systems in HeLa cells by the exogenous overexpression of one E1A mutant, which led to a lack of CBP-binding ability. Our results suggest that these two CBP-interacting sites in the GRIP AD1 domain not only determine its AD1 activity, but are also involved in its co-activator functions in some nuclear receptors.

Activating Transcription Factor 2↗
PubMed2001

Ligand-dependent formation of retinoid receptors, receptor-interacting protein 140 (RIP140), and histone deacetylase complex is mediated by a novel receptor-interacting motif of RIP140.

Receptor-interacting protein 140 (RIP140) interacts with retinoic acid receptor and retinoid X receptor in a ligand-dependent manner and suppresses retinoic acid (RA) induction of its target genes. The receptor-interacting motif is mapped to a C-terminal peptide sequence (LTKTNPILYYMLQK) of RIP140. The functional role of this motif in mediating the suppressive effects of RIP140 on RA induction is demonstrated in mutation studies. RA induces coimmunoprecipitation of histone deacetylase 3 with retinoic acid receptor/retinoid X receptor in the presence of wild type RIP140, but not in the presence of the C-terminal motif-deleted RIP140. A decrease in histone acetylation on the promoter region that carries a RA response element is associated with the expression of wild type RIP140, but not with expression of the mutant RIP140, in a dose-dependent manner. These data provide a molecular explanation for RIP140 acting as a novel ligand-dependent, negative modulator of RA-regulated gene expression.

Acetylation↗
PubMedDate not supplied

Drug interactions between opioids and antiretroviral medications: interaction between methadone, LAAM, and nelfinavir.

Understanding drug interactions between antiretrovirals and opiate therapies may decrease toxicities and enhance adherence, with improved HIV outcomes in injection drug users. We report results of a clinical pharmacology study designed to examine the interaction of the protease inhibitor, nelfinavir, with methadone and LAAM (N = 48). Nelfinavir decreased methadone exposure, but no withdrawal was observed over the five day study period. LAAM and dinorLAAM concentrations were decreased, while norLAAM concentrations were increased, with minimal overall change in LAAM/metabolite exposure. Methadone and LAAM did not affect nelfinavir concentrations, but methadone decreased M8 metabolite exposure. While no toxicities were observed, clinicians should be aware of the potential for drug interactions when patients require treatment with nelfinavir and these opiate medications.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Valproic acid-ketoconazole interaction in normal, hypoalbuminemic, and uremic sera: lack of interaction in uremic serum caused by the presence of inhibitor.

Ketoconazole is an antifungal agent widely used in the management of patients with fungal infection, especially in patients with acute acquired immuno-deficiency syndrome (AIDS). Ketoconazole is 99% bound to serum albumin and may interact with valproic acid, an anticonvulsant with 90% to 95% binding to serum albumin. The interaction may be more significant in hypoalbuminemia, a common finding in patients with AIDS. However, valproic acid-ketoconazole interaction has not been reported. The authors prepared two serum pools from patients receiving valproic acid with normal serum albumin and another pool from patients with hypoalbuminemia. Another serum pool was prepared from uremic patients not receiving valproic acid. The aliquots of serum pool were supplemented with various concentrations of ketoconazole, representing therapeutic and slightly higher therapeutic concentrations. The concentrations of free valproic acid were determined in protein-free ultrafiltrates (prepared by centrifuging specimens at 25 degrees C with the Centrifree Micropartition System at 1500 g for 20 minutes) using fluorescence polarization immunoassay. In the serum pool with normal albumin concentration, the authors observed statistically significant displacement of valproic acid only at higher ketoconazole concentrations (10 and 20 micrograms/ml) whereas, in the serum pool with hypoalbuminemia, they observed statistically significant displacement of valproic acid by ketoconazole with lower and higher concentrations of ketoconazole. The magnitude of displacement was more significant at high valproic acid concentrations (95 and 150 mg/ml, respectively) probably because of the concentration-dependent binding of valproic acid to serum albumin. The authors observed no displacement of valproic acid by ketoconazole in the uremic serum pool. On the other hand, the free valproic acid concentrations were decreased in the presence of ketoconazole in the uremic serum pool.

Anticonvulsants↗