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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A systematic investigation on possible structures of heterofullerenes C70-nPn (n=2-10) has been performed employing semiempirical MNDO and ab initio methods. The stabilities decrease with increasing number of heteroatoms. The structures whose carbon atoms are substituted in the para pattern across the equatorial hexagons correspond to the most stable isomers. The isomeric pattern of P-doped C70 systems follows our previously proposed correlation between the isomerism of the fullerene adducts C60Xn/C70Xn and those of the heterofullerenes C60-nNn or C60-nBn /C70-nNn or C70-nBn. The aromaticity of the most stable structures of heterofullerenes is studied to investigate the heteroatom doping effect on the electron delocalization of the fullerene cage.
J Mol Model 2002 Jul
PMID:Isomerism and aromaticity of heterofullerene C70-nPn (n=2-10). 1219 32

The number of intrinsically disordered proteins known to be involved in cell-signaling and regulation is growing rapidly. To test for a generalized involvement of intrinsic disorder in signaling and cancer, we applied a neural network predictor of natural disordered regions (PONDR VL-XT) to four protein datasets: human cancer-associated proteins (HCAP), signaling proteins (AfCS), eukaryotic proteins from SWISS-PROT (EU_SW) and non-homologous protein segments with well-defined (ordered) 3D structure (O_PDB_S25). PONDR VL-XT predicts >or=30 consecutive disordered residues for 79(+/-5)%, 66(+/-6)%, 47(+/-4)% and 13(+/-4)% of the proteins from HCAP, AfCS, EU_SW, and O_PDB_S25, respectively, indicating significantly more intrinsic disorder in cancer-associated and signaling proteins as compared to the two control sets. The disorder analysis was extended to 11 additional functionally diverse categories of human proteins from SWISS-PROT. The proteins involved in metabolism, biosynthesis, and degradation together with kinases, inhibitors, transport, G-protein coupled receptors, and membrane proteins are predicted to have at least twofold less disorder than regulatory, cancer-associated and cytoskeletal proteins. In contrast to 44.5% of the proteins from representative non-membrane categories, just 17.3% of the cancer-associated proteins had sequence alignments with structures in the Protein Data Bank covering at least 75% of their lengths. This relative lack of structural information correlated with the greater amount of predicted disorder in the HCAP dataset. A comparison of disorder predictions with the experimental structural data for a subset of the HCAP proteins indicated good agreement between prediction and observation. Our data suggest that intrinsically unstructured proteins play key roles in cell-signaling, regulation and cancer, where coupled folding and binding is a common mechanism.
J Mol Biol 2002 Oct 25
PMID:Intrinsic disorder in cell-signaling and cancer-associated proteins. 1238 10

Effective eradication of established tumors and generation of a lasting systemic immune response is an important goal for cancer gene immunotherapy. The method of gene delivery may also be critical for the generation of an effective antitumor response. We compared the level of transgene expression and antitumor activity of two different interleukin (IL)-12 DNA preparations (naked DNA versus DNA lipid complex). Established murine adenocarcinoma (CT26) and renal cell carcinoma (Renca) tumors in BALB/c mice were treated by direct intratumoral injection of a nonviral plasmid DNA vector encoding the murine IL-12 (mIL-12) gene, either alone (naked) or in complexes with cationic lipid. Both treatments resulted in the same percentage (87%) of mice undergoing a complete tumor regression of the CT26 tumor. For the Renca tumor model, complete tumor regression was observed in 67 and 75% of animals treated with naked mIL-12 DNA and mIL-12 DNA plus lipid, respectively. Mice that were rendered tumor free for > 50 days by mIL-12 gene therapy rejected a subsequent challenge of parental tumor cells but not of an unrelated, syngeneic tumor. The marked reduction of tumor growth in tumor-bearing mice treated with mIL-12 cDNA was associated with the augmentation of tumor-specific cytotoxic T cells, enhanced production of IFN-gamma in spleen and lymph node cells, and increased splenomegaly and lymphadenopathy. The CD8+: CD4+ ratio in tumor-infiltrating lymphocytes was significantly increased in the tumor-bearing mice treated with mIL-12 DNA alone and mIL-12 cDNA plus lipid as compared with a control vector-treated group. These results indicate that direct intratumoral gene transfer with naked nonviral IL-12 DNA provides an effective and simple method for the treatment of murine tumors, suggesting an approach for clinical application.
Mol Cancer Ther 2002 Sep
PMID:Intratumoral injection of interleukin-12 plasmid DNA, either naked or in complex with cationic lipid, results in similar tumor regression in a murine model. 1248 17

The human oncofetal antigen 5T4 (h5T4) is a transmembrane glycoprotein overexpressed by a wide spectrum of cancers, including colorectal, ovarian, and gastric, but with a limited normal tissue expression. Such properties make 5T4 an excellent putative target for cancer immunotherapy. The murine homologue of 5T4 (m5T4) has been cloned and characterized, which allows for the evaluation of immune intervention strategies in "self-antigen" in vivo tumor models. We have constructed recombinant vaccinia viruses based on the highly attenuated and modified vaccinia virus ankara (MVA strain), expressing h5T4 (MVA-h5T4), m5T4 (MVA-m5T4), and Escherichia coli LacZ (MVA-LacZ). Immunization of BALB/c and C57BL/6 mice with MVA-h5T4 and MVA-m5T4 constructs induced antibody responses to human and mouse 5T4, respectively. C57BL/6 and BALB/c mice vaccinated with MVA-h5T4 were challenged with syngeneic tumor line transfectants, B16 melanoma, and CT26 colorectal cells that express h5T4. MVA-h5T4-vaccinated mice showed significant tumor retardation compared with mice vaccinated with MVA-LacZ or PBS. In active treatment studies, inoculation with MVA-h5T4 was able to treat established CT26-h5T4 lung tumor and to a lesser extent B16.h5T4 s.c. tumors. Additionally, when C57BL/6 mice vaccinated with MVA-m5T4 were challenged with B16 cells expressing m5T4, resulting growth of the tumors was significantly retarded compared with control animals. Furthermore, mice vaccinated with MVA-m5T4 showed no signs of autoimmune toxicity. These data support the use of MVA-5T4 for tumor immunotherapy.
Mol Cancer Ther 2002 Oct
PMID:Attenuated recombinant vaccinia virus expressing oncofetal antigen (tumor-associated antigen) 5T4 induces active therapy of established tumors. 1248 37

Cachexia is a common manifestation of late stage malignancy and is characterized by anemia, anorexia, muscle wasting, loss of adipose tissue, and fatigue. Although cachexia is disabling and can diminish the life expectancy of cancer patients, there are still no effective therapies for this condition. We have examined the feasibility of using a myogenic plasmid to express growth hormone-releasing hormone (GHRH) in severely debilitated companion dogs with naturally occurring tumors. At a median of 16 days after intramuscular delivery of the plasmid, serum concentrations of insulin-like growth factor I (IGF-I), a measure of GHRH activity, were increased in 12 of 16 dogs (P < 0.01). These increases ranged from 21 to 120% (median, 49%) of the pretreatment values and were generally sustained or higher on the final evaluation. Anemia resolved posttreatment, as indicated by significant increases in mean red blood cell count, hematocrit, and hemoglobin concentrations, and there was also a significant rise in the percentage of circulating lymphocytes. Treated dogs maintained their weights over the 56-day study and did not show any adverse effects from the GHRH gene transfer. We conclude that intramuscular injection of a GHRH-expressing plasmid is both safe and capable of stimulating the release of growth hormone and IGF-I in large animals. The observed anabolic responses to a single dose of this therapy might be beneficial in patients with cancer-associated anemia and cachexia.
Mol Ther 2002 Dec
PMID:Effects of plasmid-mediated growth hormone-releasing hormone in severely debilitated dogs with cancer. 1249 79

Structures of mono-doped fullerenes, C59Xn and C59X(6mn)m (X=Bm, N+, P+, As+, Si), the isoelectronic analogues to C60 and C606m with 60 and 66 pi-electrons, have been investigated at the B3LYP/6-31G* level of density functional theory. On the basis of the computed nucleus independent chemical shifts (NICS) at the cage center and also at the center of individual rings as magnetic criteria, heterofullerenes with 60 pi-electrons are as aromatic as the parent C60, while those with 66 pi-electrons are much less aromatic than C606m. The very distinct endohedral chemical shifts of the 66 pi-electron systems may be useful to identify the heterofullerenes through their endohedral 3He NMR chemical shifts.
J Mol Model 2003 Feb
PMID:Structures and magnetic properties of mono-doped fullerenes C59Xn and C59X(6mn)m (X=Bm, N+, P+, As+, Si): isoelectronic analogues of C60 and C60(6m). 1263 9

The stabilities of five water hexamers (cyclic, boat, book, prism and cage structure) in the gas phase were investigated with the independent molecule model. In this model, the position and orientation of each water molecule within the hexamer are characterized with a translational vector and Eulerian angles, and then each molecule can move freely as a rigid body with respect to the others. Force field energy minimization yielded structures for each hexamer. Normal mode analyses were done on the five hexamers. Hydrogen bond strength in the hexamer decreases in the order: boat, cyclic, book, cage and prism. Hydrogen bond lifetimes also decrease in this order. By estimating the internal energy and the vibrational entropy of rigid-body motions, we determined the temperature dependence of the free energy for each hexamer in the range 100-350 K. Free energy of the hexamers increases in the previously mentioned order also. The most stable hexamer is the boat, and the least stable is the prism. The stabilities of the boat and the cyclic are very similar. The more planar hexamers (cyclic and boat) are more stable than the three-dimensional hexamers (cage and prism). Although the experiments of Liu et al. [Nature 381 (1996) 501] were interpreted in terms of a cage cluster, our calculations indicate boat is more likely.
J Mol Graph Model 2003 Jun
PMID:Application of the independent molecule model to the calculation of free energy and rigid-body motions of water hexamers. 1267 36

New type of carbon nanotubes-narrow nanotubes-has recently been observed with diameters of 4-5 A. It has been postulated that the narrow nanotubes are closed by fullerene fragments of C(20) and C(36). This paper presents computational results on related model nanotubes with stoichiometries such as C(80), C(84), C(96), C(108), or C(120). The computations were carried out at the PM3, AM1, SAM1, HF/3-21G, HF/4-31G, and B3LYP/6-31G(*) levels. Two C(36) fullerenes were considered, D(6h) and D(2d). At the PM3 level and with the C(84) nanotube stoichiometry, the D(2d) cage closure gave a lower energy (by 185 kcal/mol and a diameter of 5.42 A). There is another possible candidate, a C(32) cage with D(4d) symmetry (two four-membered rings). At the PM3 level and with the C(96) nanotube stoichiometry, the D(4d) closure (with a diameter of 5.43 A) had energy lower by 210 kcal/mol than that of the D(6h) nanotube closure. On the other hand, four-membered rings should not play a significant role for narrow nanotubes with a diameter of 4 A, where the dodecahedron-related closure should be exclusive. Still narrower nanotubes are briefly discussed.
J Mol Graph Model 2003 Jun
PMID:Computations of model narrow nanotubes closed by fragments of smaller fullerenes and quasi-fullerenes. 1267 38

Two types of isopentenyl diphosphate:dimethylallyl diphosphate isomerases (IDI) have been characterized at present. The long known IDI-1 is only dependent on divalent metals for activity, whereas IDI-2 requires a metal, FMN and NADPH. Here, we report the first structure of an IDI-2 from Bacillus subtilis at 1.9A resolution in the ligand-free form and of the FMN-bound form at 2.8A resolution. The enzyme is an octamer that forms a D4 symmetrical open, cage-like structure. The monomers of 45 kDa display a classical TIM barrel fold. FMN is bound only with very moderate affinity and is therefore completely lost during purification. However, the enzyme can be reconstituted in the crystals by soaking with FMN. Three glycine-rich sequence stretches that are characteristic for IDI-2 participate in FMN binding within the interior of the cage. Regions harboring strictly conserved residues that are implicated in substrate binding or catalysis remain largely disordered even in the presence of FMN.
J Mol Biol 2003 Jun 20
PMID:Crystal structure of the type II isopentenyl diphosphate:dimethylallyl diphosphate isomerase from Bacillus subtilis. 1279 87

alpha 1 Adrenergic receptors mediate a variety of physiological responses and have been well studied in the cardiovascular and peripheral nervous system. However, their role in the central nervous system remains ill defined because of the lack of highly specific ligands to the alpha1 receptor subtypes. Here, we have employed gene targeting to elucidate the role of alpha 1d receptors in vivo. In addition to disrupting function, the insertion of the lacZ gene into the alpha 1d receptor locus enabled the specific identification of cells expressing the alpha 1d gene. These cells are localized in the cortex, hippocampus, olfactory bulb, dorsal geniculate and ventral posterolateral nuclei of the thalamus. Behaviorally, the alpha 1d(-/-) mice show normal locomotor activity during the subjective day, or resting phase of their cycle. However, during subjective night, or active phase, wheel-running activity is significantly reduced in mutant mice. Furthermore, these mice show a reduction in exploratory rearing behavior in a novel cage environment. Lastly, alpha 1d(-/-) mice show reduced hyperlocomotion after acute amphetamine administration. Together, these data reveal the functional importance of alpha 1d adrenoceptors in mediating a variety of stimulus-induced changes in locomotor behaviors. While the sensitivity of noradrenergic neurons to environmental stimuli has been well documented, our data demonstrate that at least some of these post-synaptic responses are mediated by alpha 1d adrenergic receptors.
Mol Psychiatry 2003 Jul
PMID:alpha 1d Adrenoceptor signaling is required for stimulus induced locomotor activity. 1287 2


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