Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cardiac activity of a series of analogues of the positive inotropic bipyridines amrinone (5-amino-[3,4'-bipyridin]-6(1H)-one) and milrinone (2-methyl-5-cyano-[3,4'-bipyridin]-6(1H)-one) was evaluated in vitro in a rabbit myocardial membrane Mg(2+)-dependent, Ca(2+)-stimulable adenosine triphosphatase (Ca(2+)-ATPase) model and structure-activity relationships were compared for nine closely related derivatives. In the present studies, a 5-bromo analogue of milrinone stimulated myocardial membrane Ca(2+)-ATPase significantly (10(-7) M; P < 0.001 vs control, with 67% of the activity of milrinone), whereas a 2'-methyl-2H-milrinone derivative was inactive. Although amrinone was inactive in this assay, its 2-methyl analogue was stimulatory. However, analogues lacking a 2-substituent (with or without a 5-cyano group) or with the 3-N position blocked by a methyl group did not stimulate myocardial membrane Ca(2+)-ATPase activity. Structural data for these bipyridines show that those with either a 2- or 2'-methyl substituent have a twist conformation, whereas those without are nearly planar. Activity data reveal that those bipyridines with a nonplanar conformation are more active in the Ca(2+)-ATPase assay. Further study of milrinone analogues with a 2'-methyl substituent shows that even though the effect on the twist angle is equivalent to that of 2-methyl substitution, these analogues are less potent. Data for this series reveal that the prerequisites for Ca(2+)-ATPase stimulation include not only a 2-methyl to maintain a twist conformation but also a free 3-N position and a 5-substituent. This model for optimal activity in the myocardial membrane Ca(2+)-ATPase system differs from those proposed for phosphodiesterase enzyme receptor recognition only in the requirement for a nonplanar molecule. We have previously shown that milrinone, but not amrinone, shares structural homology with thyroxine and was able to stimulate myocardial membrane Ca(2+)-ATPase activity in a manner similar to the thyroid hormone. Additionally, milrinone, but not amrinone, was an effective competitor for thyroxine binding to the serum transport protein transthyretin. Analysis of the milrinone-transthyretin crystal complex confirms the structural homology between milrinone and thyroid hormone which is not shared by amrinone. Modeling studies of the binding interactions of milrinone analogues indicate that the 2-desmethylmilrinone analogue, the most inhibitory analogue, lacks the hydrophobic contacts present in milrinone in its transthyretin-bound complex.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Structure-activity relationships of milrinone analogues determined in vitro in a rabbit heart membrane Ca(2+)-ATPase model. 778 30

Sarcoplasmic reticulum-enriched membranes from rabbit skeletal muscle contained Ca(2+)-ATPase activity which was significantly enhanced (26% increase, P < 0.001) in vitro by physiological concentrations (10(-10) M) of L-thyroxine (T4) and 3,3',5-triiodo-L-thyronine (T3). In contrast, the biologically inactive iodothyronine analogues D-T4 and 3,3',5,5'-tetraiodothyroacetic acid (Tetrac) (10(-10) M) were without effect on enzyme activity. 3,5-Dimethyl-3'-isopropyl-L-thyronine (Dimit), a bioactive analogue, was highly effective as a Ca(2+)-ATPase stimulator, increasing enzyme activity by 43% (P < 0.02 vs. T4 effect). A bipyridine cardiac inotropic agent, milrinone, has been reported to be thyromimetic in a myocardial membrane Ca(2+)-ATPase system, and in concentrations from 10(-10) to 10(-5) M enhanced skeletal muscle SR membrane Ca(2+)-ATPase activity in vitro (P < 0.001). Milrinone analogues which have been previously shown to enhance rabbit myocardial membrane Ca(2+)-ATPase activity, and which have a twist relationship of the pyridine rings, were also striated muscle Ca(2+)-ATPase stimulators. We conclude that (1) striated muscle is a mammalian tissue in which physiological levels of biologically relevant thyroid hormone analogues, particularly Dimit, stimulate Ca(2+)-ATPase activity in vitro by a non-genomic mechanism; (2) cardiac bipyridine analogues which are thyromimetic in vitro in rabbit heart, and which have structural homologies with thyroid hormone, are stimulators of rabbit striated muscle sarcoplasmic reticulum Ca(2+)-ATPase activity.
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PMID:Rabbit skeletal muscle sarcoplasmic reticulum Ca(2+)-ATPase activity: stimulation in vitro by thyroid hormone analogues and bipyridines. 827 88

The study of higher order chromosome structure and how it is modified through the course of the cell cycle has fascinated geneticists, biochemists, and cell biologists for decades. The results from many diverse technical avenues have converged in the discovery of a large superfamily of chromosome-associated proteins known as SMCs, for structural maintenance of chromosomes, which are predicted to have ATPase activity. Now found in all eukaryotes examined, and numerous prokaryotes as well, SMCs play crucial roles in chromatid cohesion, chromosome condensation, sex chromosome dosage compensation, and DNA recombination repair. In eukaryotes, SMCs exist in five subfamilies, which appear to associate with one another in particular pairs to perform their specific functions. In this review, we summarize current progress examining the roles these proteins, and the complexes they form, play in chromosome metabolism. We also present a twist in the SMC story, with the possibility of one SMC moonlighting in an unpredicted location.
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PMID:Review: SMCs in the world of chromosome biology- from prokaryotes to higher eukaryotes. 1080 64

The ATPase ISWI is the molecular motor of several remodeling factors that trigger nucleosome sliding in vitro. In search for the underlying mechanism, we found that unilateral binding of ISWI to a model nucleosome correlated with directional movement of the nucleosome toward the enzyme. It has been proposed that ISWI might loosen histone-DNA interactions through twisting DNA. However, nucleosome sliding assays on nicked DNA substrates suggest that propagation of altered twist is not involved. Surprisingly, nicks in the linker DNA in front of the nucleosome facilitate sliding. These data suggest that the rate of nucleosome sliding is limited by a conformational change other than twisting, such as the formation of a short loop, of DNA at the entry into the nucleosome.
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PMID:ISWI induces nucleosome sliding on nicked DNA. 1174 43

Chromatin-remodeling complexes couple ATP hydrolysis to alterations in histone-DNA interactions and nucleosome mobility, allowing transcription factors access to chromatin. Here, we use triple-helix strand-displacement assays, DNA length-dependent ATPase assays, and DNA-minicircle ATPase assays to establish that RSC, as well as its isolated ATPase subunit Sth1, are DNA translocases. RSC/Sth1 ATPase activity is stimulated by single-stranded DNA, suggesting that Sth1 tracks along one strand of the DNA duplex. Each RSC complex appears to contain a single molecule of Sth1, and isolated Sth1 is capable of nucleosome remodeling. We propose that the remodeling enzyme remains in a fixed position on the octamer and translocates a segment of DNA (with accompanying DNA twist), which breaks histone-DNA contacts and propagates as a wave of DNA around the octamer. The demonstration of DNA translocation presented here provides a mechanistic basis for this DNA wave. To test the relative contribution of twist to remodeling, we use nucleosomes containing nicks in precise locations to uncouple twist and translocation. Nucleosomes bearing nicks are remodeled less efficiently than intact nucleosomes. These results suggest that RSC and Sth1 are DNA translocases that use both DNA translocation and twist to remodel nucleosomes efficiently.
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PMID:Chromatin remodeling by RSC involves ATP-dependent DNA translocation. 1218 66

During the ATP hydrolysis cycle of the Dictyostelium myosin II motor domain, two conserved alpha-helices, the SH1/SH2 helix and the relay helix, rotate in a coordinated way to induce the swing motion of the converter domain. A network of hydrophobic and ionic interactions in these two helices and the converter may ensure that the motions of these helices are effectively transmitted to the converter. To examine the roles of these interactions in the ATPase-dependent converter swing, we disrupted two conserved hydrophobic linkages among them by means of a point mutation (I499A or F692A). The resulting mutations induced only limited changes in the kinetic parameters of ATP hydrolysis, except for a marked increase of basal MgATPase activity. However, the mutant myosins completely lost their in vitro and in vivo motor functions. Measurements of the intrinsic tryptophan fluorescence and the GFP-based FRET revealed that the converter domain of these mutants did not swing during steady-state ATP hydrolysis or in the presence of tightly trapped Mg.ADP.V(i), which shows that the point mutations induced the uncoupling of the converter swing and ATP hydrolysis cycle. These results highlight the importance of these hydrophobic linkages for transmitting the coordinated twist motions of the helices to the converter as well as the requirement of this converter swing for force generation.
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PMID:Dictyostelium myosin II mutations that uncouple the converter swing and ATP hydrolysis cycle. 1251 42

Smc2/4 forms the core of the Saccharomyces cerevisiae condensin, which promotes metaphase chromosome compaction. To understand how condensin manipulates DNA, we used two in vitro assays to study the role of SMC (structural maintenance of chromosome) proteins and ATP in reconfiguring the path of DNA. The first assay evaluated the topology of knots formed in the presence of topoisomerase II. Unexpectedly, both wild-type Smc2/4 and an ATPase mutant promoted (+) chiral knotting of nicked plasmids, revealing that ATP hydrolysis and the non-SMC condensins are not required to compact DNA chirally. The second assay measured Smc2/4-dependent changes in linking number (Lk). Smc2/4 did not induce (+) supercoiling, but instead induced broadening of topoisomer distributions in a cooperative manner without altering Lk(0). To explain chiral knotting in substrates devoid of chiral supercoiling, we propose that Smc2/4 directs chiral DNA compaction by constraining the duplex to retrace its own path. In this highly cooperative process, both (+) and (-) loops are sequestered (about one per kb), leaving net writhe and twist unchanged while broadening Lk. We have developed a quantitative theory to account for these results. Additionally, we have shown at higher molar stoichiometries that Smc2/4 prevents relaxation by topoisomerase I and nick closure by DNA ligase, indicating that Smc2/4 can saturate DNA. By electron microscopy of Smc2/4-DNA complexes, we observed primarily two protein-laden bound species: long flexible filaments and uniform rings or "doughnuts." Close packing of Smc2/4 on DNA explains the substrate protection we observed. Our results support the hypothesis that SMC proteins bind multiple DNA duplexes.
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PMID:The Saccharomyces cerevisiae Smc2/4 condensin compacts DNA into (+) chiral structures without net supercoiling. 1610 Jan 11

The contractile ring and the cell cortex generate force to divide the cell while maintaining symmetrical shape. This requires temporal and spatial regulation of the actin cytoskeleton at these areas. We force-expressed misregulated versions of actin-binding proteins, tropomyosin and caldesmon, into cells and analyzed their effects on cell division. Cells expressing proteins that increase actomyosin ATPase, such as human tropomyosin chimera (hTM5/3), significantly speed up division, whereas cells expressing proteins that inhibit actomyosin, such as caldesmon mutants defective in Ca(2+)/calmodulin binding (CaD39-AB) and in cdk1 phosphorylation sites (CaD39-6F), divide slowly. hTM5 and hTM5/3-expressing cells lift one daughter cell off the substrate and twist. Furthermore, CaD39-AB- and CaD39-6F-expressing cells are sensitive to hypotonic swelling and show severe blebbing during division, whereas hTM5/3-expressing cells are resistant to hypotonic swelling and produce membrane bulges. These results support a model where Ca(2+)/calmodulin and cdk1 dynamically control caldesmon inhibition of tropomyosin-activated actomyosin to regulate division speed and to suppress membrane blebs.
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PMID:Tropomyosin and caldesmon regulate cytokinesis speed and membrane stability during cell division. 1685 66

The ClpB chaperone forms a hexamer ring and rescues aggregated proteins in co-operation with the DnaK system. Each subunit of ClpB has two nucleotide-binding modules, AAA (ATPase associated with various cellular activities)-1 and AAA-2, and an 85-A (1 A=0.1 nm)-long coiled-coil. The coiled-coil consists of two halves: wing-1, leaning toward AAA-1, and wing-2, leaning away from all the domains. The coiled-coil is stabilized by leucine zipper-like interactions between leucine and isoleucine residues of two amphipathic alpha-helices that twist around each other to form each wing. To destabilize the two wings, we developed a series of mutants by replacing these residues with alanine. As the number of replaced residues increased, the chaperone activity was lost and the hexamer became unstable. The mutants, which had a stable hexameric structure but lost the chaperone activities, were able to exert the threading of soluble denatured proteins through their central pore. The destabilization of wing-1, but not wing-2, resulted in a several-fold stimulation of ATPase activity. These results indicate that stability of both wings of the coiled-coil is critical for full functioning of ClpB, but not for the central-pore threading of substrate proteins, and that wing-1 is involved in the communication between AAA-1 and AAA-2.
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PMID:Stability of the two wings of the coiled-coil domain of ClpB chaperone is critical for its disaggregation activity. 1935 26

Chromatin remodelers are multifunctional protein machines that use a conserved ATPase motor to slide nucleosomes along DNA. Nucleosome sliding has been proposed to occur through two mechanisms: twist diffusion and loop/bulge propagation. A central idea for both of these models is that a DNA distortion propagates over the surface of the nucleosome. Recent data from biochemical and single-molecule experiments have expanded our understanding of histone-DNA and remodeler-nucleosome interactions, and called into question some of the basic assumptions on which these models were originally based. Advantages and challenges of several nucleosome sliding models are discussed.
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PMID:Mechanisms of ATP-dependent nucleosome sliding. 2006 Jul 7


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