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Cashman DJ Buscaglia R Freyer MW Dettler J Hurley LH Lewis EA 《Journal of molecular modeling》2008,14(2):93-101
G-Quadruplex and i-Motif-forming sequences in the promoter regions of several oncogenes show promise as targets for the regulation
of oncogenes. In this study, molecular models were created for the c-MYC NHE-III1 (nuclease hypersensitivity element III1) from two 39-base complementary sequences. The NHE modeled here consists of single folded conformers of the polypurine intramolecular
G-Quadruplex and the polypyrimidine intramolecular i-Motif structures, flanked by short duplex DNA sequences. The G-Quadruplex
was based on published NMR structural data for the c-MYC 1:2:1 loop isomer. The i-Motif structure is theoretical (with five
cytosine–cytosine pairs), where the central intercalated cytosine core interactions are based on NMR structural data obtained
for a tetramolecular [d(A2C4)4] model i-Motif. The loop structures are in silico predictions of the c-MYC i-motif loops. The porphyrin meso-tetra(N-methyl-4-pyridyl)porphine
(TMPyP4), as well as the ortho and meta analogs TMPyP2 and TMPyP3, were docked to six different locations in the complete
c-MYC NHE. Comparisons are made for drug binding to the NHE and the isolated G-Quadruplex and i-Motif structures. NHE models
both with and without bound cationic porphyrin were simulated for 100 ps using molecular dynamics techniques, and the non-bonded
interaction energies between the DNA and porphyrins calculated for all of the docking interactions.
Figure Molecular models of the average structure of the final 20 ps of the molecular dynamics simulation of the c-MYC NHE-III1 (nuclease hypersensitivity element III1) “silencer” element. The G-Quadruplex structure is at the top-center, and the i-Motif is at the bottom-center of each picture.
a “Rotation #1” of the G-Quadruplex, with the T15 loop at the top and rear and the G19/A20 loop at the top and front of the picture. b “Rotation #2” of the G-Quadruplex, with the T15 loop at the top and front of the image, and the G19/A20 loop at the front and adjacent to the G-Quadruplex/i-Motif interface 相似文献
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Defining the molecular basis of the DNA sequence selectivity of polyamine binding is central to understanding polyamine-dependent gene expression. We have studied, by selective NMR experiments, the variation of spermine mobility and conformation in the presence of G-quadruplexes formed by sequences of the purine-rich strand of the c-Myc promoter, nuclease hypersensitivity element III1 (NHE III1). All the NHE quadruplexes restrict spermine mobility and induce a spermine conformational change but the most effective immobilisation occurs when all five G-tracts of the NHE III1 are present. This suggests structure within the nucleotides flanking the G-quadruplex has a role in immobilising spermine. 相似文献
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We studied the structures and stabilities of G-quadruplexes formed in Myc1234, the region containing the four consecutive 5' runs of guanines of c-MYC promoter NHE III(1,) which have recently been shown to form in a supercoiled plasmid system in aqueous solution. We determined the NMR solution structure of the 1:2:1 parallel-stranded loop isomer, one of the two major loop isomers formed in Myc1234 in K(+) solution. This major loop isomer, although sharing the same folding structure, appears to be markedly less stable than the major loop isomer formed in the single-stranded c-MYC NHE III(1) oligonucleotide, the Myc2345 G-quadruplex. Our NMR structures indicated that the different thermostabilities of the two 1:2:1 parallel c-MYC G-quadruplexes are likely caused by the different base conformations of the single nucleotide loops. The observation of the formation of the Myc1234 G-quadruplex in the supercoiled plasmid thus points to the potential role of supercoiling in the G-quadruplex formation in promoter sequences. We also performed a systematic thermodynamic analysis of modified c-MYC NHE III(1) sequences, which provided quantitative measure of the contributions of various loop sequences to the thermostabilities of parallel-stranded G-quadruplexes. This information is important for understanding the equilibrium of promoter G-quadruplex loop isomers and for their drug targeting. 相似文献
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Secondary structure in transfer RNA genes 总被引:3,自引:0,他引:3
The bacterial strand of the heteroduplex of λh80 dglyTsu+36tyrTthrT with λh80 carries a cluster of three transfer RNA genes. The bacterial strands of the heteroduplexes of φ80hpsu+,?III and φ80hpsu?III with φ80h carry two and one genes for tyrosine tRNA, respectively. When these heteroduplexes are spread under weakly denaturing conditions (low formamide), secondary structure features consisting of one or several closely clustered, short duplex regions (folds) are observed. The features map at the positions of the tRNA gene clusters. They are not seen if the DNA is hybridized to Escherichia coli tRNA. It is concluded that the secondary structure features are due to self-complementary sequences in the tRNA genes. In some cases, the duplex folds appear to involve base pairing between sequences on different tRNA genes of a cluster and may also involve the spacer sequences between the tRNA sequences. 相似文献
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Köster S Pavkov-Keller T Kühlbrandt W Yildiz Ö 《The Journal of biological chemistry》2011,286(47):40954-40961
The ubiquitous mammalian Na+/H+ exchanger NHE1 has critical functions in regulating intracellular pH, salt concentration, and cellular volume. The regulatory C-terminal domain of NHE1 is linked to the ion-translocating N-terminal membrane domain and acts as a scaffold for signaling complexes. A major interaction partner is calmodulin (CaM), which binds to two neighboring regions of NHE1 in a strongly Ca2+-dependent manner. Upon CaM binding, NHE1 is activated by a shift in sensitivity toward alkaline intracellular pH. Here we report the 2.23 Å crystal structure of the NHE1 CaM binding region (NHE1CaMBR) in complex with CaM and Ca2+. The C- and N-lobes of CaM bind the first and second helix of NHE1CaMBR, respectively. Both the NHE1 helices and the Ca2+-bound CaM are elongated, as confirmed by small angle x-ray scattering analysis. Our x-ray structure sheds new light on the molecular mechanisms of the phosphorylation-dependent regulation of NHE1 and enables us to propose a model of how Ca2+ regulates NHE1 activity. 相似文献
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A series of carboxylate-bridged manganese(III) complexes derived from Schiff bases obtained by the condensation of salicylaldehyde or 5-bromo-salicylaldehyde and different types of diamine have been synthesized and characterized and, in the case of [Mn2(L1)2(μ-ClCH2COO)](ClO4) (1), the structure has been obtained by X-ray crystallography. The structure of 1 consists of two manganese atoms separated by 5.487(3) Å and bridged by a carboxylate anion. This dinuclear structural unit is linked by bridging phenoxy oxygens to adjacent dinuclear units to produce a one-dimensional chain. Cyclic voltammograms of all the compounds exhibit grossly similar features consisting of a reversible or quasi-reversible MnIII/MnII reduction and a MnIII/MnIV oxidation. It has been observed that bromo-substitution stabilizes the lower oxidation state in the MnIII/MnII couple and destabilizes the higher oxidation state in the MnIII/MnIV couple. Variable temperature magnetic susceptibility measurements of 1 show a weak antiferromagnetic interaction. The magnetic behavior is satisfactorily modeled by inclusion of zero-field splitting and an intermolecular interaction component. 相似文献
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Gül Şimşek Richard D. Vaughan-Jones Pawel Swietach H. Burak Kandilci 《Journal of cellular physiology》2019,234(4):4681-4694
The heart is highly active metabolically but relatively underperfused and, therefore, vulnerable to ischemia. In addition to acidosis, a key component of ischemia is hypoxia that can modulate gene expression and protein function as part of an adaptive or even maladaptive response. Here, using cardiac-derived HL-1 cells, we investigate the effect of various hypoxic stimuli on the expression and activity of Na+/H + exchanger 1 (NHE1), a principal regulator of intracellular pH. Acute (10 min) anoxia produced a reversible decrease in the sarcolemmal NHE1 activity attributable to NHE1 internalization. Treatment with either 1% O 2 or dimethyloxaloylglycine (DMOG; 1 mM) for 48-hr stabilized hypoxia-inducible factor 1 and reduced the sarcolemmal NHE1 activity by internalization, but without a change in total NHE1 immunoreactivity or message levels of the coding gene ( SLC9A1) determined in whole-cell lysates. Unlike the effect of DMOG, which was rapidly reversed on washout, reoxygenation after a prolonged period of hypoxia did not reverse the effects on NHE1, unless media were also supplemented with a membrane-permeant derivative of glutathione (GSH). Without a prior hypoxic episode, GSH supplementation had no effect on the NHE1 activity. Thus, posthypoxic NHE1 reinsertion can only take place if cells have a sufficient reservoir of a reducing agent. We propose that oxidative stress under prolonged hypoxia depletes intracellular GSH to an extent that curtails NHE1 reinsertion once the hypoxic stimulus is withdrawn. This effect may be cardioprotective, as rapid postischaemic restoration of the NHE1 activity is known to trigger reperfusion injury by producing an intracellular Na +-overload, which is proarrhythmogenic. 相似文献
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Na+/H+ exchanger NHE1 and NHE2 have opposite effects on migration velocity in rat gastric surface cells
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Anja Paehler vor der Nolte Giriprakash Chodisetti Zhenglin Yuan Florian Busch Brigitte Riederer Min Luo Yan Yu Manoj B. Menon Andreas Schneider Renata Stripecke Katerina Nikolovska Sunil Yeruva Ursula Seidler 《Journal of cellular physiology》2017,232(7):1669-1680
Following superficial injury, neighbouring gastric epithelial cells close the wound by rapid cell migration, a process called epithelial restitution. Na+/H+ exchange (NHE) inhibitors interfere with restitution, but the role of the different NHE isoforms expressed in gastric pit cells has remained elusive. The role of the basolaterally expressed NHE1 (Slc9a1) and the presumably apically expressed NHE2 (Slc9a2) in epithelial restitution was investigated in the nontransformed rat gastric surface cell line RGM1. Migration velocity was assessed by loading the cells with the fluorescent dye DiR and following closure of an experimental wound over time. Since RGM1 cells expressed very low NHE2 mRNA and have low transport activity, NHE2 was introduced by lentiviral gene transfer. In medium with pH 7.4, RGM1 cells displayed slow wound healing even in the absence of growth factors and independently of NHE activity. Growth factors accelerated wound healing in a partly NHE1‐dependent fashion. Preincubation with acidic pH 7.1 stimulated restitution in a NHE1‐dependent fashion. When pH 7.1 was maintained during the restitution period, migratory speed was reduced to ~10% of the speed at pH 7,4, and the residual restitution was further inhibited by NHE1 inhibition. Lentiviral NHE2 expression increased the steady‐state pHi and reduced the restitution velocity after low pH preincubation, which was reversible by pharmacological NHE2 inhibition. The results demonstrate that in RGM1 cells, migratory velocity is increased by NHE1 activation, while NHE2 activity inhibit this process. A differential activation of NHE1 and NHE2 may therefore, play a role in the initiation and completion of the epithelial restitution process. 相似文献
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Using bis(3,5-dimethylpyrazol-1-yl)methane as an N-N donor ligand, a trans-[RuIII(N-N)2Cl2]+ core has been isolated from the direct reaction of the ligand with RuCl3 · xH2O and characterized structurally for the first time. The core displays a rhombic EPR spectrum and a quasireversible Ru(II/III) couple with an E1/2 of −0.34 V versus NHE. 相似文献
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