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1.
We have developed a versatile computer program for optimization of ligand binding experiments (e.g., radioreceptor assay system for hormones, drugs, etc.). This optimization algorithm is based on an overall measure of precision of the parameter estimates (D-optimality). The program DESIGN uses an exact mathematical model of the equilibrium ligand binding system with up to two ligands binding to any number of classes of binding sites. The program produces a minimal list of the optimal ligand concentrations for use in the binding experiment. This potentially reduces the time and cost necessary to perform a binding experiment. The program allows comparison of any proposed experimental design with the D-optimal design or with assay protocols in current use. The level of nonspecific binding is regarded as an unknown parameter of the system, along with the affinity constant (Kd) and binding capacity (Bmax). Selected parameters can be fixed at constant values and thereby excluded from the optimization algorithm. Emphasis may be placed on improving the precision of a single parameter or on improving the precision of all the parameters simultaneously. We present optimal designs for several of the more commonly used assay protocols (saturation binding with a single labeled ligand, competition or displacement curve, one or two classes of binding sites), and evaluate the robustness of these designs to changes in parameter values of the underlying models. We also derive the theoretical D-optimal design for the saturation binding experiment with a homogeneous receptor class.  相似文献   

2.
We have developed a computer program, DESIGN, for optimization of ligand binding experiments to minimize the "average" uncertainty in all unknown parameters. An earlier report [G. E. Rovati, D. Rodbard, and P. J. Munson (1988) Anal. Biochem. 174, 636-649] described the application of this program to experiments involving a single homologous or heterologous dose-response curve. We now present several advanced features of the program DESIGN, including simultaneous optimization of two or more binding competition curves optimization of a "multiligand" experiment. Multiligand designs are those which use combinations of two (or more) ligands in each reaction tube. Such designs are an important and natural extension of the popular method of "blocking experiments" where an additional ligand is used to suppress one or more classes of sites. Extending the idea of a dose-response curve, the most general multiligand design would result in a "dose-response surface". One can now optimize the design not only for a single binding curve, but also for families of curves and for binding surfaces. The examples presented in this report further demonstrate the power and utility of the program DESIGN and the nature of D-optimal designs in the context of more complex binding experiments. We illustrate D-optimal designs involving one radioligand and two unlabeled ligands; we consider one example of homogeneous and several examples of heterogeneous binding sites. Further, to demonstrate the virtues of the dose-response surface experiment, we have compared the optimal surface design to the equivalent design restricted to traditional dose-response curves. The use of DESIGN in conjunction with multiligand experiments can improve the efficiency of estimation of the binding parameters, potentially resulting in reduction of the number of observations needed to obtain a desired degree of precision in representative cases.  相似文献   

3.
An extensive Monte Carlo study has been carried out in order to study the effect of measurement error on the precision of parameter estimates of an insulin binding system. Hypothetical radioimmunoassay experiments were generated for insulin binding to erythrocytes. The design of experiments followed strictly the protocol of real experiments. Randomly generated error was added to the synthetic data. The standard technique, a weighted non-linear regression analysis, was employed to re-estimate parameters of a model of two receptor sites and a model of negative co-operativity. As the original parameter values were known, the differences between original and estimated values was studied for (a) measurement error in the range from 0-17%, (b) random initial estimates and (c) error-free non-specific binding. In addition, analytical estimates of parameter precision were compared with the true between-experiment variation of parameter estimates. At the measurement error of 12%, a one site model is recommended to estimate the high affinity population of the two sites model. Plausible results can be expected in 90% of experiments, the between-experiment variation being approximately 30%. The model of two receptor sites gives approximately two thirds of plausible results. The high affinity population can be estimated with the between-experiment variation of 40%, the low affinity population is virtually unidentifiable with the between-experiment variation of approximately 100% and parameter estimates biased to higher values. Only half of the results obtained from the model of negative co-operativity are plausible, the variation in parameter estimates ranges from 90-150% and estimates are biased to higher values. At the level of 12% measurement error, random initial estimates do not significantly affect the estimation process, provided initial estimates are selected from a feasible range. At the same measurement error, the error-free non-specific binding does not improve the results, indicating that the mean of six replicates may be taken as a reliable estimate of non-specific binding. The analytical estimates of the coefficient of variation systematically underestimates the true between-experiments coefficient of variation, the difference has been found to be about 50%.  相似文献   

4.
The dog platelet alpha-adrenergic receptor was characterized using [3H]clonidine and [3H]yohimbine. The binding of both radioligands was rapid and reversible at 25 degrees C; saturation and kinetic experiments revealed a single population of binding sites. The number of [3H]yohimbine sites was 2-3-fold higher than the number of [3H]clonidine sites as reported in other tissues containing alpha2-adrenoceptors. The various alpha-agonists and antagonists displaced [3H]clonidine and [3H]yohimbine with an order of potency indicating alpha2-adrenoceptor specificity. Neither (-)adrenaline nor clonidine infusions (0.5 micrograms/min/kg during 3 hr) modified the number of [3H]yohimbine and [3H]clonidine sites or the affinity of the ligands for the alpha2-sites of the dog platelet. Oral administration of clonidine (3 X 150 micrograms/day) did not alter the binding parameters of either ligand.  相似文献   

5.
Abstract

Monte Carlo simulations have been applied for evaluating the reliability of parameter estimates as well as for testing models in radioligand saturation binding experiments. Scatchard analysis was compared to the nonlinear least-square curve fitting method for one-site saturation binding curves. It was found that linear regression analysis from the transformed data in the Scatchard plot yielded generally less accurate parameter estimates than nonlinear regression analysis of untransformed data. The advantage of the nonlinear least-squares curve fitting method was especially pronounced in cases where the scatter and number of data points, as well as the radioligand concentration range, were chosen similar to less optimal experimental conditions. Under such circumstances, several KD and Bmax values derived by Scatchard analysis led to physically impossible negative values whereas the same data analyzed by nonlinear regression yielded reasonable parameter estimates. Furthermore, it was found that for both means of analysis, KD and Bmax correlated positively. In another set of Monte Carlo experiments, saturation binding curves involving two receptor sites were generated and subsequently analyzed according to both a one-site and a two-site model. The confidence with which one is able to distinguish the two-site model from nonlinear least-squares curve fitting was then estimated for optimal, as well as for, less ideal experimental condigions.  相似文献   

6.
We have tested the hypothesis that smaller alpha1B-adrenoceptor labeling by [3H]tamsulosin compared to [3H]prazosin is related to differential recognition of agonist low affinity states. Paired saturation binding experiments with [3H]prazosin and [3H]tamsulosin were performed in membrane preparations from rat liver and Rat- fibroblasts stably transfected with wild-type hamster alpha1B-adrenoceptors or a constitutively active mutant thereof. In all three settings [3H]tamsulosin labeled significantly fewer alpha1B-adrenoceptors than [3H]prazosin. In noradrenaline competition binding experiments, the percentage of agonist low affinity sites was smallest for the constitutively active alpha1B-adrenoceptor but the percentage of agonist low affinity sites recognized by [3H]tamsulosin and [3H]prazosin did not differ significantly. We conclude that [3H]tamsulosin labels fewer alpha1B-adrenoceptors than [3H]prazosin but this is not fully explained by a poorer labeling of agonist low affinity sites.  相似文献   

7.
Indenestrol A (IA), an oxidative metabolite of the synthetic estrogen diethylstilbestrol (DES), has high binding affinity for estrogen receptor in mouse uterine cytosol but possesses weak biological activity. Racemic mixture of optically active [3H]indenestrol A (IA-Rac) was separated and purified into individual enantiomers on a semi-preparative scale by HPLC with a Chiralpak OP(+) column. The structure-activity relationship was investigated among the [3H]IA enantiomers (IA-R and IA-S) and [3H]DES through direct saturation binding assays using mouse uterine cytosol. Specific binding curves and Scatchard plots were obtained for each [3H]ligand; DES, IA-Rac, IA-R and IA-S. IA-S enantiomer (Kd = 0.67) binds to the estrogen receptor with the same affinity as DES (Kd = 0.71) and four times higher affinity than IA-R (Kd = 2.56). The number of binding sites for IA-S is approximately the same as estradiol, DES and IA-Rac while IA-R binds far fewer sites than the other ligands. Saturation binding assays indicated that [3H]DES and [3H]IA enantiomers exhibited a higher level of non-specific binding to the cytosol receptor compared to estradiol which has a low level of non-specific binding. These binding studies led to the detection of an additional binding component for the stilbestrol compounds in estrogen target tissue cytosol preparations. Sucrose density gradient separation assays under low salt conditions showed that both [3H]DES and [3H]IA compounds bound to the 8S form of the receptor, the same as E2. But, in addition both DES and IA bound to another binding component in 4S region. The binding to the 4S component were partially displaced by the addition of excess unlabeled E2 and DES. Further characterization of the 4S component is described.  相似文献   

8.
The present study demonstrates that [3H]imipramine binds to both high- and low-affinity imipramine binding components on membranes prepared from rat cerebral cortex. Scatchard and computer analyses of saturation experiments using a wide range of [3H]imipramine concentrations (0.5 nM-50 nM) revealed the presence of two binding components. Inhibition experiments in which membranes were incubated with [3H]imipramine and various concentrations of unlabelled imipramine gave shallow inhibition curves with a Hill coefficient of 0.60 +/- 0.04. When dissociation rates of imipramine were studied, biphasic dissociation curves were obtained with apparent half-times of dissociation of 2.5 +/- 0.4 min and 18.5 +/- 2.5 min. Thus analysis of saturation, competition, and dissociation experiments indicate that [3H]imipramine binds to low as well as high-affinity binding sites in rat cortex.  相似文献   

9.
In saturation binding experiments, (+)pentazocine, (+)3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP), haloperidol and rimcazole did not inhibit the binding of [3H]DTG in a purely competitive fashion. Although Scatchard analysis indicated that [3H]DTG bound to a single site, the inhibition curves of some, but not all, reference compounds exhibited Hill coefficients of less than 0.8. The Scatchard data were consistent with a model of hyperbolic competitive inhibition of binding to the [3H]DTG-defined sigma site, although other possibilities such as negative cooperativity or binding to two sites cannot be definitively excluded. Compounds from numerous pharmacological and structural classes inhibited the binding of [3H]DTG, suggesting that interactions of [3H]DTG with other receptors may have confounded the Scatchard analysis of the binding of [3H]DTG to sigma recognition sites.  相似文献   

10.
[3H]-RX 781094 and [3H]-rauwolscine, two potent alpha 2-adrenergic antagonists, were used to characterize alpha 2 receptor in basolateral membranes from rabbit kidney. However, the following findings suggest that the imidazoline [3H]-RX 781094 binds to an heterogeneous population of binding sites: 1) dissociation plot was biphasic with a fast and slow component, 2) in saturation experiments, [3H]-RX 781094 labels 3.5 more binding sites than [3H]-rauwolscine (p less than 0.02), 3) competition studies showed that molecules with imidazoline structure completely inhibited the [3H] RX 781094 binding; in contrast, only 25% of binding was affected by non-imidazoline alpha 2 adrenergic compounds. These results suggest that in basolateral membranes from rabbit kidney, [3H] RX781094 labels alpha 2 adrenergic and non-adrenergic receptors which might be imidazoline-preferring binding sites.  相似文献   

11.
The binding of [3H]neurotensin to membranes from human brain at 0 degrees C was specific, saturable, and reversible. In the frontal cortex, the equilibrium dissociation constant (KD) for [3H]neurotensin determined from the ratio of rate constants (k-1/k1), saturation isotherms, and inhibition binding experiments was 0.80, 2.0, and 2.0 nM, respectively, and the maximum number of binding sites (Bmax) from the saturation isotherms and the competitive binding experiments was 2.4 and 2.2 pmol/g of tissue, respectively. Hill coefficients for binding were equal to 1, indicating the presence of single, noncooperative binding sites. Inhibition of specific binding of [3H]-neurotensin by several analogs of neurotensin showed that [Gln4]neurotensin and neurotensin(8-13) had the highest affinities for these binding sites in human frontal cortex, with each analog being approximately 13-fold more potent than neurotensin. In addition, these data showed that the carboxy-terminal portion of neurotensin played an important part in the binding of this neuropeptide in human brain, a result described for other species. Regional distribution of binding sites was different from that reported for animal brains. Of the 33 different regions investigated, the uncus and substantia nigra showed the highest specific binding of [3H]neurotensin, whereas such areas as the pineal body, medulla, and corpus callosum had few binding sites.  相似文献   

12.
Rat pheochromocytoma PC 12 cell membranes were shown to possess A2-like adenosine binding sites as assessed by using 5'-N-ethylcarboxamide[3H]adenosine [( 3H]NECA). Specific [3H]NECA binding to PC 12 cell membrane at 0 degrees C was saturable and showed a monophasic saturation profile. In contrast, [3H]NECA binding to PC 12 cell membrane at 30 degrees C exhibited a biphasic profile suggesting the presence of two specific binding site. The rank order of potency for inhibition of [3H]NECA binding at 0 degrees C was NECA greater than 2-chloroadenosine greater than 2',5'-dideoxyadenosine greater than isobutylmethylxanthine much greater than phenylisopropyladenosine. These adenosine binding sites were solubilized with sodium cholate and the solubilized portion retained the same ligand binding characteristics as those of the membrane-bound form. Gel filtration experiments indicated an apparent Stokes radius of 6.7 nm for these adenosine binding sites/detergent complexes.  相似文献   

13.
The binding of [3H]PAF-acether (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) to intact human gel-filtered platelets was measured at 22 degrees C. Specific binding reached saturation within 15 min at high doses of [3H]PAF-acether (0.5-0.9 nM), whereas about 90 min were required when low doses (0.02-0.5 nM) were used. Above 1 nM, [3H]PAF-acether non-specific binding increased progressively, which together with the demonstration of a 3H-labelled metabolite suggested uptake and metabolism of [3H]PAF-acether. Equilibrium analysis revealed one class of specific receptors with a Ka of 18.86 +/- 4.82 X 10(9) M-1 and 242 +/- 64 binding sites per platelet. Non-equilibrium binding revealed a similar Ka (16.87 X 10(9) M-1). Specific binding became irreversible after prolonged incubation, a process that was enhanced at increasing concentrations of [3H]PAF-acether. Platelets made desensitized to PAF-acether by prior incubation with unlabelled PAF-acether failed to bind a second dose of PAF-acether (3H-labelled), suggesting that desensitization resulted from loss of available binding sites. Under the conditions of the binding studies, PAF-acether induced exposure of the fibrinogen receptor, aggregation (in a stirred suspension) and alterations in (poly)-phosphatidylinositides. These results suggest that PAF-acether initiates platelet responses via receptor-mediated processes.  相似文献   

14.
Abstract

[3H]ICS 205–930 labelled 5-HT3 recognition sites in membranes prepared from murine neuroblastoma N1E-115 cells. Binding was rapid, reversible, saturable and stereoselective to an apparently homogeneous population of sites. Kinetic studies revealed that agonists and antagonists produced a monophasic dissociation reaction of [3H]ICS 205–930 from its recognition sites. The dissociation rate constant of the radioligand was similar whether the dissociation was induced by an agonist or an antagonist. Competition studies carried out with agonists and antagonists also suggested the presence of a homogeneous population of [3H]ICS 205–930 recognition sites. Competition curves were best fit for a 1 site model. [3H]ICS 205–930 binding sites displayed the pharmacological profile of a 5-HT3 receptor. The interactions of agonists and antagonists with [3H]ICS 205–930 recognition sites were apparently competitive in nature, as demonstrated in kinetic and equilibrium experiments. In saturation experiments carried out with [3H]ICS 205–930 in the presence and the absence of unlabelled agonists and antagonists, apparent Bmax values were not reduced whereas apparent Kd values were increased in the presence of competing ligands. There was a good agreement between apparent pKB values calculated for the competing ligands in saturation experiments and pKd values calculated from competition experiments. The present data demonstrate that [3H]ICS 205–930 labels a homogeneous population of sites at which agonists and antagonists interact competitively.  相似文献   

15.
Homogeneity or heterogeneity of rat soleus-muscle Na,K-ATPase (Na+ + K+-dependent ATPase) with respect to affinity for [3H]ouabain was evaluated. Since the standard method for measuring specific [3H]ouabain binding to rat skeletal-muscle samples includes subtraction of a value for non-specific [3H]ouabain uptake and retention, and a wash-out in the cold to remove [3H]ouabain from the extracellular phase, it was possible that these procedures could hide a class of [3H]ouabain-binding sites either with low affinity or with a rapid dissociation of [3H]ouabain. However, measurements of [3H]ouabain uptake and retention over the range 0.1-5 mM, as well as the omission of wash-out, gave no evidence for heterogeneity of [3H]ouabain-binding sites in rat soleus muscle. Furthermore, the observation of agreement between the uptake and retention of non-specific [3H]ouabain and of [14C]sucrose gave no evidence for the existence of a major pool of [3H]ouabain-binding sites with low affinity for [3H]ouabain. Assuming homogeneity, the total concentration of [3H]ouabain binding sites in soleus-muscle samples from 12-week-old rats is 278-359 pmol/g wet wt.  相似文献   

16.
The availability of the bispenicillamine enkephalin [3H] [D-Pen2,D-Pen5]enkephalin ([3H]DPDPE) a highly selective ligand for delta-opioid receptors, has made possible a more definitive examination of the ontogeny of this receptor subtype. In this report, the binding characteristics of [3H]DPDPE in 5-day-old neonatal (P-5) and adult rat brain are compared. Analysis of saturation curves as well as homologous displacement data revealed no significant difference in the binding affinity of [3H]DPDPE between P-5 animals and adults. Conversely, the binding capacity increased fivefold during this period. The delta-specificity of the sites was further proven by competition experiments with mu- and delta-selective ligands. Mn2+ (0.5 mM) elevated [3H]DPDPE specific binding by lowering the Kd, whereas 50 microM 5'-guanylylimidodiphosphate inhibited it by decreasing the total number of high-affinity binding sites in both P-5 animals and adults. Pertussis toxin-catalyzed ADP ribosylation experiments revealed the presence of 40-kDa proteins, with a molecular mass corresponding to G protein subunits alpha i/alpha o, as early as 1 h after birth. There was a low, but detectable, basal low-Km GTPase activity in P-5 animals, which increased fivefold during postnatal development. The present report establishes the existence of high-affinity [3H]DPDPE binding as well as GTP-regulatory proteins 5 days after birth. Yet, heterologous competition studies and ionic effects suggest that neonatal binding sites differ from adult receptors. Whether the neonatal sites are newly synthesized, incompletely processed sites or a developmentally programmed isoform remains to be determined.  相似文献   

17.
A binding assay for muscarinic cholinergic receptors has been developed using labelled dexetimide as ligand and a filtration technique. The main features of this assay are its stereospecific nature, the very high affinity of the ligand for the specific receptors sitcs and its very low affinity for non-specific binding sites. The latter point was further investigated using labelled levitimide, the inactive enantiomer. The binding was found to be neither stereospecific nor saturable and displacement by both enantiomers revealed a particular curve with a very flattened course. Kinetic experiments with [3H]dexetimide suggest the occurrence of a heterogenous population of muscarinic receptors in the rat striatum. A study of the regional distribution of muscarinic receptors in rat brain showed a high concentration in the dopaminergic areas, the cortex and the hippocampus, but practically none in the cerebellum. The subcellular distribution pattern revealed a marked enrichment of [3H]dexetimide stereospecific binding sites in the microsomal fraction of rat striatum and hippocampus. Such a distribution was not found with [3H]levitimide. All the characteristics of this binding assay make dexetimide a very appropriate ligand for labelling muscarinic receptors in vitro as well as in vivo.  相似文献   

18.
Three pharmacologically distinct high-affinity [3H]serotonin ([3H]5-HT) binding sites were identified in spinal cord synaptosomes. [3H]5-HT competition studies using selective 5-HT1A receptor ligands indicated that approximately 25% of high-affinity synaptosomal [3H]5-HT binding was inhibited by 5-HT1A-selective compounds, an estimate consistent with [3H](+-)-8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) saturation experiments in which 5-HT1A receptors were directly labeled. [3H]5-HT competition studies using high-affinity 5-HT1B compounds performed in the presence of 100 nM 8-OH-DPAT (to block 5-HT1A receptors) indicated that approximately 26% of all specific, high-affinity [3H]5-HT binding to spinal cord synaptosomes was to 5-HT1B receptors. [3H]5-HT competition studies performed in the presence of 100 nM 8-OH-DPAT and 10 nM RU 24969 (to block 5-HT1A and 5-HT1B receptors, respectively) indicated that the remaining 49% of [3H]5-HT binding did not possess the pharmacologic profile previous reported for 5-HT1C, 5-HT1D, 5-HT1E, 5-HT2, or 5-HT3 receptors. This residual 49% of [3H]5-HT binding to spinal cord synaptosomes observed in the presence of 100 nM 8-OH-DPAT and 10 nM RU 24969 (subsequently referred to as "5-HT1S") displayed high affinity and saturability (KD = 4.7 nM) in association/dissociation and saturation experiments. Addition of 300 microM GTP or the nonhydrolyzable form of GTP, 5'-guanylylimidodiphosphate, inhibited [3H]5-HT binding to 5-HT1S receptors in saturation experiments by 35 and 57%, respectively, whereas ATP was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   

19.
Abstract

Analysis of (-)[125]iodo-N6-(4-hydroxyphenylisopropyl)-adenosine ([125I]HPIA) binding to purified sarcolemmal preparations of guinea pig and bovine hearts revealed two classes of binding sites when unlabeled iodo-HPIA (100 μmol/1) was used as non-specific binding marker. In the presence of 1 mmol/1 theophylline, however, only the high affinity component was detected. Adenosine receptor agonists caused biphasic displacement of [125I]HPIA binding, with a high affinity potency rank order typical of interaction with A1-adenosine receptors. Biphasic competition curves were also observed with 8-phenyltheophylline and isobutylmethylxanthine, whereas the theophylline curve was monophasic up to 1 mmol/1. In brain membranes, specific binding of [125I]HPIA as well as of [3H]PIA was further reduced when unlabeled iodo-HPIA replaces theophylline as the non-specific binding marker. These results suggest the presence of two [125I]HPIA binding sites on cardiac sarcolemma and brain membranes, but receptor function can only be ascribed to the high affinity sites. The low affinity site probably represents an artefact, which is often observed when non-specific binding is defined with the unlabeled counterpart or a structurally related ligand of the radioligand used.  相似文献   

20.
The characteristics of [3H]hemicholinium-3 ([3H]HC-3) interactions with rat striatal membranes were investigated. Under the described assay conditions, [3H]-HC-3 binds with a saturable population of membrane binding sites having the following regional distribution: striatum much greater than hippocampus greater than or equal to cerebral cortex greater than cerebellum. The specific binding of [3H]HC-3 showed an obligatory requirement for NaCl; other halide salts of sodium or KCl failed to substitute for NaCl. The Scatchard transformation of saturation isotherm data generated a curvilinear plot with high- and low-affinity components of binding. The dissociation of [3H]HC-3 at infinite dilution was also multiexponential. The dissociation could, however, be accelerated if unlabeled HC-3 was included in the diluting buffer, and this increase in dissociation appeared to be dependent on the concentrations of unlabeled HC-3 used, with the maximal increase demonstrable at 100 nM. The dissociation was also dependent on the fractional saturation of binding sites with labeled HC-3, such that, at higher fractional saturation of binding sites, the overall dissociation was faster and the difference in the dissociation observed between "dilution only" and "dilution + unlabeled HC-3" was reduced. This occupancy-dependent change in dissociation could also be influenced by temperature and pH. Based on the results of these kinetic studies, the steady-state [3H]HC-3 binding data were analyzed for a homogeneous population of binding sites undergoing site-site interactions of the negative cooperative type. Such an analysis yielded a KD of 9.3 nM for the high-affinity state and a KD of 22.8 nM for the low-affinity state of binding sites, with a Bmax of 434 fmol/mg of protein. Competitive binding studies showed that unlabeled HC-3 was most potent in displacing [3H]HC-3, followed by choline. Other drugs known to have little influence on the synaptosomal sodium-dependent high-affinity choline uptake system (SDHACU) had no significant effect on [3H]HC-3 binding sites. Similarities in ionic dependencies, regional distributions, and pharmacological selectivities of [3H]HC-3 binding with synaptosomal SDHACU suggest that [3H]HC-3 selectively labels SDHACU sites located on presynaptic cholinergic neurons in rat CNS. We suggest that the two affinity states of [3H]HC-3 binding sites represent the different "functional" states of the SDHACU system. The binding of HC-3 (or choline) with the high-affinity state of the binding sites induces negative cooperative site-site interactions among the binding sites, resulting in the formation of a low-affinity binding state.(ABSTRACT TRUNCATED AT 400 WORDS)  相似文献   

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