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PubMed1988

Dimerization of the tat protein from human immunodeficiency virus: a cysteine-rich peptide mimics the normal metal-linked dimer interface.

We have synthesized an 18-amino acid peptide that contains the cysteine-rich region of the tat protein from human immunodeficiency virus. Previous experiments in vitro with the intact tat protein have shown that these cysteines serve as metal ligands, causing tat to form metal-linked dimers. Ultraviolet absorption spectra show that the synthetic peptide (tat21-38) binds two Cd2+ or two Zn2+ ions per peptide monomer, and some changes in the circular dichroism spectra are seen as the metals bind. The peptide-metal complexes are completely resistant to proteolytic digestion, and mass spectrometry demonstrates that this peptide forms metal-linked dimers. The peptide can also combine with the intact tat protein to form metal-linked heterodimers. If these heterodimers are unable to trans-activate viral transcription, tat21-38 could be a lead compound for designing drugs to treat acquired immunodeficiency syndrome.

Amino Acid Sequence↗
PubMed1989

Camelliin B and nobotanin I, macrocyclic ellagitannin dimers and related dimers, and their antitumor activity.

Camelliin B and nobotanin I, dimeric hydrolyzable tannins of a new class having macrocyclic structures, were isolated from Camellia japonica and Heterocentron roseum, respectively. Nobotanin G and H of the structures related to nobotanin I, were also obtained from H. roseum. Camelliin B and also woodfordin C, a macrocyclic dimer from Woodfordia fruticosa, exhibited marked host-mediated antitumor activities.

Animals↗
PubMed1990

Woodfordin C, a macro-ring hydrolyzable tannin dimer with antitumor activity, and accompanying dimers from Woodfordia fruticosa flowers.

Three new dimeric hydrolyzable tannins, woodfordins A, B and C, along with seven known hydrolyzable tannins, including oenothein B, a dimer exhibiting marked host-mediated antitumor activity, were isolated from an Indonesian crude drug, Sidowayah [dried flowers of Woodfordia fruticosa (L.) Kurz (Lythraceae)]. The structures of the new tannins were elucidated based on chemical and spectral evidence. Woodfordin C, having a macro-ring structure, was also found to exhibit a significant antitumor activity.

Animals↗
PubMed1992

DNA-induced dimerization of the Escherichia coli rep helicase. Allosteric effects of single-stranded and duplex DNA.

The Escherichia coli Rep helicase is a stable monomer (Mr = 72,802) in the absence of DNA; however, binding of single-stranded (ss) or duplex (ds) DNA induces Rep monomers to dimerize. Furthermore, a chemically cross-linked Rep dimer retains both its DNA-dependent ATPase and helicase activities, suggesting that the functionally active Rep helicase is a dimer (Chao, K., and Lohman, T. M. (1991) J. Mol. Biol. 221, 1165-1181). Using a modified "double-filter" nitrocellulose filter binding assay, we have examined quantitatively the equilibrium binding of Rep to a series of ss-oligodeoxynucleotides, d(pN)n (8 less than or equal to n less than or equal to 20) and two 16-base pair duplex oligodeoxynucleotides, which are short enough so that only a single Rep monomer can bind to each oligonucleotide. This strategy has enabled us to examine the linkage between DNA binding and dimerization. We also present a statistical thermodynamic model to describe the DNA-induced Rep dimerization in the presence of ss- and/or ds-oligodeoxynucleotides. We observe quantitative agreement between this model and the experimental binding isotherms and have analyzed these isotherms to obtain the seven independent interaction constants that describe Rep-DNA binding and Rep dimerization. We find that Rep monomers (P) can bind either ss-DNA (S) or ds-DNA (D) to form PS or PD, respectively, which can then dimerize to form P2S or P2D. Furthermore, both protomers of the DNA-induced Rep dimer can bind DNA to form either P2S2, P2D2 or the mixed dimer species P2SD and ss- and ds-DNA compete for the same sites on the Rep protein. When bound to DNA, the Rep dimerization constants are approximately 1-2 x 10(8) M-1 (6 mM NaCl, pH 7.5, 4 degrees C), which are greater than the dimerization constant for free Rep monomers by at least 10(4)-fold. The Rep-ss-DNA interaction constants are independent of base composition and sequence, consistent with its role as a nonspecific DNA-binding protein. Allosteric effects are associated with ss- and ds-DNA binding to the half-saturated Rep dimers, i.e. the affinity of either ss- or ds-DNA to the free promoter of a half-saturated Rep dimer is clearly influenced by the conformation of DNA bound to the first protomer. These allosteric effects further support the proposal that the Rep dimer is functionally important and that the Rep-DNA species P2S2 and P2SD may serve as useful models for intermediates that occur during DNA unwinding.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphatases↗
PubMed1976

Tetramer-dimer dissociation in homoglobin and the Bohr effect.

The pH dependence of the apparent tetramer to dimer dissociation constant has been determined at 20 degrees for both oxy- and deoxyhemoglobins A and Kansas. These measurements were made by three different procedures: gel chromatography, sedimentation velocity, and kinetic methods in either of three buffer systems: 0.05 M cacodylate, Tris, or glycine with 1 mM EDTA and 0.1 M NaCl between pH 6.5 and 11. The tetramer-dimer dissociation constant of human oxyhemoglobin A decreases from about 3.2 X 10(-6) M at pH 6.0 to about 3.2 X 10(-8) M at pH 8.5. The slope of this line indicates that the dissociation of tetramer to dimer is accompanied by the uptake of about 0.6 protons per mol of tetramer in this region. The corresponding dissociation constant for deoxyhemoglobin in the same pH region increases apparently almost linearly from 1.0 x 10(-12) M at pH 6.5 to about 1.0 x 10(-5) M at pH 11. To dimer is associated with the release of about 1.6 protons per mol of tetramer. Comparison of these data with the known proton release accompanying the oxygenation of tetramers confirms that the pH dependence of oxygen binding by dimers must be very small. The present data predict that the overall proton release or uptake per oxygen bound by dimer should be less than 0.1. The tetramer-dimer dissociation equilibria of oxy- and deoxyhemoglobins above pH 8.5 have identical pH dependences. In this range the dissociation constant of deoxy-Hb is about one-tenth that of oxyhemoglobin. Human oxyhemoglobin Kansas is known to have an enhanced tetramer-dimer dissociation compared with that of hemoglobin A. Below pH 8.5 the tetramer-dimer dissociation constant of Hb Kansas is about 400 times greater than that of HbA in the absence of phosphate buffers. In contrast, the tetramer-dimer dissociation constants of deoxyhemoglobins A and Kansas appear to be identical. These findings are consistent with previous structural observations on these hemoglobins. The data on the tetramer-dimer dissociation of human hemoglobin were used to calculate the total free energy of binding of oxygen to the tetramer and the median oxygen pressure on the basis of fundamental linkage relations and a pH-independent estimate of the total free energy of binding oxygen to dimer. Simulated oxygen binding curves were generated with the equations of Ackers and Halvorson (Ackers, G. K., and Halvorson, H. (1974) Proc. Natl. Acad. Sci. U.S.A. 71, 4312-4316) by making two assumptions: (a) that the dimers are noncooperative and pH-independent in O2 binding and (b) that the distribution of cooperative energy in the oxygenation of tetramers is independent of pH. We have compared these simulations with experimental data obtained at low protein concentrations (30 to 124 muM heme) to show that the variation in oxygen affinity with pH can be described in terms of the subunit equilibria. We conclude that an accurate analysis of the contributions of individual oxygen binding steps to the Bohr effect cannot be made without considering the contributions of the dimers to oxygen binding...

Hemoglobins↗
PubMed1991

Site-specific effect of thymine dimer formation on dAn.dTn tract bending and its biological implications.

dAn.dTn sequences, otherwise known as A tracts, are hotspots for cis-syn thymine dimer formation and deletion mutations induced by UV light. Such A tracts are also known to bend DNA, suggesting that some biological effects of UV light might be related to the distinctive structure and properties of cis-syn dimer-containing A tracts. To investigate the effect of thymine dimer formation on A-tract bending multimers of all possible dimer monoadducts of a dA6.dT6-containing decamer known to bend DNA were prepared along with multimers of a dimer-containing 21-mer of heterogeneous sequence. The characteristic anomalous electrophoretic behavior of the phased A-tract multimers was essentially abolished by dimer formation at the center of the A tract and was only slightly reduced by dimer formation at the ends. These effects are attributed to disruption of the A-tract structure at the site of the dimer, resulting in intact A tracts of reduced length and, hence, reduced bending. This model was suggested by the ability to formulate the estimated bend angles of the dimer-containing A tracts as approximately equal to the sum of the bend angles induced by the dimer and the remaining intact portion of the A tract. Contrary to a previous experimental study that concluded that the thymine dimer bends DNA by approximately 30 degrees, the dimer was determined to bend DNA by only approximately 7 degrees. Reduction of the bending of a DNA sequence by dimer formation may have a number of unpredicted and important biological consequences.

Base Composition↗
PubMed1990

A study of the dimer formation of Rous sarcoma virus RNA and of its effect on viral protein synthesis in vitro.

The genetic material of all retroviruses examined so far is an RNA dimer where two identical RNA subunits are joined at their 5' ends by a structure named dimer linkage structure (DLS). Since the precise location and structure of the DLS as well as the mechanism and role(s) of RNA dimerization remain unclear, we analysed the dimerization process of Rous sarcoma virus (RSV) RNA. For this purpose we set up an in vitro model for RSV RNA dimerization. Using this model RSV RNA was shown to form dimeric molecules and this dimerization process was greatly activated by nucleocapsid protein (NCp12) of RSV. Furthermore, RSV RNA dimerization was performed in the presence of complementary 5'32P-DNA oligomers in order to probe the monomer and dimer forms of RSV RNA. Data indicated that the DLS of RSV RNA probably maps between positions 544-564 from the 5' end. In an attempt to define sequences needed for the dimerization of RSV RNA, deletion mutageneses were generated in the 5' 600 nt. The results showed that the dimer promoting sequences probably are located within positions 208-270 and 400-600 from the 5' end and hence possibly encompassing the cis-acting elements needed for the specific encapsidation of RSV genomic RNA. Also it is reported that synthesis of the polyprotein precursor Pr76gag is inhibited upon dimerization of RSV RNA. These results suggest that dimerization and encapsidation of genome length RSV RNA might be linked in the course of virion formation since they appear to be under the control of the same cis elements, E and DLS, and the trans-acting factor nucleocapsid protein NCp12.

Avian Sarcoma Viruses↗
PubMed1992

Analytical study of avian reticuloendotheliosis virus dimeric RNA generated in vivo and in vitro.

The retroviral genome consists of two identical RNA molecules associated at their 5' ends by a stable structure called the dimer linkage structure. The dimer linkage structure, while maintaining the dimer state of the retroviral genome, might also be involved in packaging and reverse transcription, as well as recombination during proviral DNA synthesis. To study the dimer structure of the retroviral genome and the mechanism of dimerization, we analyzed features of the dimeric genome of reticuloendotheliosis virus (REV) type A and identified elements required for its dimerization. Here we report that the REV dimeric genome extracted from virions and infected cells, as well as that synthesized in vitro, is more resistant to heat denaturation than avian sarcoma and leukemia virus, murine leukemia virus, or human immunodeficiency virus type 1 dimeric RNA. The minimal domain required to form a stable REV RNA dimer in vitro was found to map between positions 268 and 452 (KpnI and SalI sites), thus corresponding to the E encapsidation sequence (J. E. Embretson and H. M. Temin, J. Virol. 61:2675-2683, 1987). In addition, both the 5' and 3' halves of E are necessary in cis for RNA dimerization and the extent of RNA dimerization is influenced by viral sequences flanking E. Rapid and efficient dimerization of REV RNA containing gag sequences in addition to the E sequences and annealing of replication primer tRNA(Pro) to the primer-binding site necessitate the nucleocapsid protein.

3T3 Cells↗
PubMed1990

D-dimer and TAT measurement in patients with deep venous thrombosis: utility in diagnosis and judgement of anticoagulant treatment effectiveness.

The plasma levels of thrombin-antithrombin III-complexes (TAT) and the fibrin split product D-Dimer were measured in 39 patients with phlebographically proven acute DVT: 34 patients had proximal DVT, 5 had calf DVT. The sensitivity of D-Dimer and TAT measurements in the diagnosis of proximal DVT was found to be dependent on the duration of symptoms: 0 to 7 days (n = 27): elevated D-Dimer levels (greater than 120 ng/ml) = 1, D-Dimer Latex test positive (greater than 500 ng/ml) = 1, elevated TAT levels (greater than 6 ng/ml) = 0.88. Eight to 14 days (n = 7): elevated D-Dimer levels = 1, D-Dimer Latex test positive = 0.33, elevated TAT levels = 0.66; specificity: elevated D-Dimer: 0.48, D-Dimer Latex test: 1, elevated TAT: 0.76. Calf DVT patients (n = 5) had elevated D-Dimer levels, negative Latex tests and 3 of them had normal TAT values. Hemostatic and fibrinolytic parameters were also determined in 13 patients during heparin treatment of proximal DVT. Elevated D-Dimer and TAT levels rapidly decreased after initiation of anticoagulant therapy. In 2 of 13 patients a marked increase in D-Dimer and TAT levels was observed in periods of ineffective heparinization, documented by normal or only slightly prolonged thrombin clotting times. We conclude from our results that 1) D-Dimer EIA measurement, in contrast to TAT measurement, shows a very high sensitivity in the diagnosis of DVT, 2) due to low specificity this test can only be used to exclude thrombosis in patients with suspected DVT, and 3) the determination of the plasma levels of D-Dimer and TAT may be useful for judging the effect of anticoagulant treatment on thrombotic processes.

Adult↗
PubMed1990

Chloranil-photosensitized monomerization of dimethylthymine cyclobutane dimers and effect of magnesium perchlorate.

The photosensitized monomerization of the cyclobutane dimers of 1,3-dimethylthymine by p-chloranil was investigated by means of steady-state irradiation and laser-flash photolysis. Quantum yields for the monomerization are 0.34 for the cis,syn dimer, 0.39 for the trans,syn dimer, and much less than 10(-2) for the cis,anti isomer. Formation of the chloranil anion radical associated with quenching of triplet chloranil by the dimers demonstrates that electron transfer from dimers to triplet chloranil occurs to initiate the monomerization. Kinetic analysis suggested that the syn-dimer cation radicals undergo the ring cleavage at greater than or equal to 10(9) s-1 before escaping from the solvent cage, while the reactivity of the anti-dimer cation radical is very low. The different reactivities of the syn and anti dimer cation radicals are discussed in terms of through-bond coupling between the n orbitals of N(1) and N(1') involving the cyclobutane-ring sigma orbitals. In the cases of the syn-dimers, the sensitizer-dimer ion-radical pairs undergo the rapid geminate recombination that works as a major energy dissipating channel responsible for the lower-than-unity quantum yields. It has been found that the presence of Mg(ClO4)2 at 0.1 M enhances approximately 1.5 times either the monomerization of the syn dimers or the formation of the chloranil anion radical. A laser-flash photolysis study shows that Mg2+ forms a complex with either the triplet or the anion radical of chloranil. The net salt effects are attributed to the retardation of the rapid geminate recombination by the participation of Mg2+ in the sensitizer-dimer ion-radical pairs.

Chloranil↗
PubMed1990

Photo-CIDNP detection of pyrimidine dimer radical cations in anthraquinonesulfonate-sensitized splitting.

Anthraquinone-2-sulfonate (AQS) photosensitizes pyrimidine dimer splitting. Electron abstraction from the dimer is thought to induce dimer splitting, but direct evidence for the existence and intermediacy of dimer radical cations has been lacking. By employing photochemically induced dynamic nuclear polarization, we have found emission signals in the NMR spectra of dimers upon photolysis of dimers in the presence of anthraquinone-2-sulfonate. The two dimers employed were cis, syn-thymine dimer in which the N(1)-positions were linked by a three-carbon bridge and the N(3), N(3')-dimethyl derivative of that compound. The anthraquinone-2-sulfonate sensitized photochemically induced dynamic nuclear polarization spectrum of the methylated derivative exhibited an emission signal from the dimer-C(6) hydrogens. This result implied the existence of a dimer radical cation (mD+.) formed by electron abstraction by excited anthraquinone-2-sulfonate and nuclear spin sorting within a solvent caged radical ion pair [mD+. AQS-.]. Product pyrimidine photochemically induced dynamic nuclear polarization signals were also seen [enhanced absorption by C(6)-hydrogens and emission by C(5)-methyl groups]. Nuclear spin polarization in the product resulted from spin sorting in one or more of its precursors, including mD+. The results support the conclusion that dimer radical cations not only exist but are intermediates in the photosensitized splitting of pyrimidine dimers by anthraquinonesulfonate.

Anthraquinones↗
PubMed1992

A new class of bradykinin antagonists: synthesis and in vitro activity of bissuccinimidoalkane peptide dimers.

A systematic study on the dimerization of the bradykinin (BK) antagonist D-Arg0-Arg1-Pro2-Hyp3-Gly4-Phe5-Ser6-D-Phe 7-Leu8-Arg9 has been performed. The first part of this study involved compounds wherein dimerization was carried out by sequentially replacing each amino acid with cysteine and cross-linking with bismaleimidohexane. The second part of this study utilized a series of bissuccinimidoalkane dimers wherein the intervening methylene chain was varied systematically from n = 2 to n = 12 while the point of dimerization was held constant at position 6. The biological activities of these dimers were then evaluated on BK-induced smooth muscle contraction in two different isolated tissue preparations: guinea pig ileum (GPI) and rat uterus (RU). Several of the dimeric BK antagonists displayed remarkable activities and long durations of action. In addition, dimerization at position 4, 7, 8, or 9 produced dimeric analogues with markedly reduced potency. Rank order of antagonist potency as a function of dimerization position is as follows: rat uterus, 6 greater than 5 greater than 0 greater than 2 greater than 1 greater than 3 much greater than 4, 7, 8, 9; guinea pig ileum, 6 greater than 5 greater than 3 greater than 2 greater than 1 greater than 0 much greater than 4, 7, 8, 9. Evaluation of the linker length as represented by the number of methylene units indicated an optimal distance between the two monomeric peptides of six to eight methylene moieties. These studies also revealed that the carbon-chain length significantly affected the duration of action in vitro and resulted in partial agonism effects when n greater than 8. The optimum activity in vitro was achieved with dimerization at position 6 and n = 6 (designated herein as compound 25; alternatively, CP-0127). Similar effects in potency were also seen when the monomeric antagonist D-Arg0-Arg1-Pro2-Hyp3-Gly4-Phe5-Ser6-D-Phe 7-Phe8-Arg9 (NPC-567) was dimerized using similar chemistry. These results suggest that the development of BK antagonists of significant therapeutic potential may be possible using a dimerization strategy that can overcome the heretofore limiting problems of potency and in vivo duration of action found with many of the BK antagonists in the literature.

Amino Acid Sequence↗