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1.
Molecular Probing of the HPV-16 E6 Protein Alpha Helix Binding Groove with Small Molecule Inhibitors
Anne Rietz Dino P. Petrov Matthew Bartolowits Marsha DeSmet V. Jo Davisson Elliot J. Androphy 《PloS one》2016,11(2)
The human papillomavirus (HPV) HPV E6 protein has emerged as a central oncoprotein in HPV-associated cancers in which sustained expression is required for tumor progression. A majority of the E6 protein interactions within the human proteome use an alpha-helix groove interface for binding. The UBE3A/E6AP HECT domain ubiquitin ligase binds E6 at this helix-groove interface. This enables formation of a trimeric complex with p53, resulting in destruction of this tumor suppressor. While recent x-ray crystal structures are useful, examples of small molecule probes that can modulate protein interactions at this interface are limited. To develop insights useful for potential structure-based design of ligands for HPV E6, a series of 2,6-disubstituted benzopyranones were prepared and tested as competitive antagonists of E6-E6AP helix-groove interactions. These small molecule probes were used in both binding and functional assays to evaluate recognition features of the E6 protein. Evidence for an ionic functional group interaction within the helix groove was implicated by the structure-activity among the highest affinity ligands. The molecular topographies of these protein-ligand interactions were evaluated by comparing the binding and activities of single amino acid E6 mutants with the results of molecular dynamic simulations. A group of arginine residues that form a rim-cap over the E6 helix groove offer compensatory roles in binding and recognition of the small molecule probes. The flexibility and impact on the overall helix-groove shape dictated by these residues offer new insights for structure-based targeting of HPV E6. 相似文献
2.
Narrative transportation is described as a state of detachment that arises when one becomes immersed in the narrative of a story. Participants viewed either an intact version of an engaging 20 min film, “Bang You’re Dead!,” (1961) by Alfred Hitchcock (contiguous condition), or a version of the same film with scenes presented out of order (noncontiguous condition). In this latter condition, the individual scenes were intact but were presented out of chronological order. Participants were told a cover story that we were interested in the amount of gun violence depicted in films. Both groups were given the goal to remember to lift their hand every time they heard the word “gun” spoken during the film. Results revealed that participants were significantly less likely to remember to execute their goal in the contiguous condition, presumably because this narrative transported viewers’ attention and thereby “hijacked” processing resources away from internal goals. 相似文献
3.
R. H. Elliot 《BMJ (Clinical research ed.)》1918,2(3026):730-731
4.
Willoughby de Broke Rudyard Kipling Hugh Elliot E. Ray Lankester Leonard Hill Laurence R. Philipps Wm. Arbuthnot Lane James Crichton-Browne H. Bryan Donkin Francis Lloyd R. A. Lyster John MacAlister F. W. Mott William Osler C. W. Saleeby J. H. Sequeira Humphry Rolleston Hugh Wansey Bayly 《BMJ (Clinical research ed.)》1919,2(3074):725
5.
R. H. Elliot 《BMJ (Clinical research ed.)》1931,1(3655):132-133
6.
Alteration of the Pathogenicity of Pasteurella pneumotropica for the Murine Lung Caused by Changes in Pulmonary Antibacterial Activity 总被引:7,自引:0,他引:7
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Pasteurella pneumotropica is a potential pulmonary pathogen in mice. In healthy animals, this organism was killed rapidly by the normal function of the intrapulmonary phagocytic defense mechanisms. Impairment of this bactericidal activity by the acute renal failure of nephrectomy resulted in multiplication of the Pasteurella in the lung, both when the animals were nephrectomized first and then infected, and when the animals were infected first and nephrectomized several hours after the infection. The study demonstrates that the pathogenicity of the Pasteurella organisms is governed by the functional state of these pulmonary antibacterial mechanisms. 相似文献
7.
Wolfgang Heinemeyer Ilka Buchmann Dave W. Tonge John D. Windass Juliane Alt-Moerbe Elmar W. Weiler Thomas Botz Joachim Schröder 《Molecular & general genetics : MGG》1987,210(1):156-164
Summary
Tzs and ipt are two Ti plasmid genes coding for proteins with isopentenyltransferase (IPT) activity in vitro. We cloned both genes for protein expression in Escherichia coli and in Agrobacterium tumefaciens, and we investigated differences between the two genes by analysing the properties of the proteins in vitro and in vivo. In vitro, extracts with tzs or ipt-coded proteins had high IPT activity, and the enzymes were identical in most properties. The most important difference was detected in vivo: the tzs-encoded protein was very active in cytokinin production, while the ipt protein required overexpression in order to obtain measurable activity in bacteria. In both cases, rans-zeatin was the major product of the gene activity. Formation of this cytokinin requires a hydroxylase function in addition to the IPT reaction. No such activity could be ascribed to tzs or ipt-encoded proteins in vitro or in vivo, but cytokinin hydroxylase activity was detected in cells and extracts of E. coli, regardless of the presence or absence of the cytokinin genes. Based on these results it is proposed that both genes code for a single enzyme activity (isopentenyltransferase), that the genes and proteins are adapted for function either in bacteria (tzs) or in transformed plant cells (ipt), and that in both prokaryotic and eukaryotic cells hydroxylation to trans-zeatin is a function contributed by host enzymes.Abbreviations DMAPP
dimethylallylpyrophosphate
- iP
isopentenyladenine
- iPA
isopentenyladenosine
- iPMP
isopentenyladenosine 5-monophosphate
- IPT
isopentenyltransferase
-
trans-Z
trans-zeatin 相似文献
8.
Robert Finney Michael Ellis Carol Langtimm Elliot Rosen Richard Firtel David R. Soll 《Developmental biology》1987,120(2):561-576
During development of Dictyostelium discoideum, cells acquire the capacity to rapidly recapitulate morphogenesis. Therefore, when cells at the loose aggregate stage are disaggregated and challenged to reaggregate, they do so in a tenth of the original time. If loose aggregate cells are disaggregated and resuspended in buffered dextrose solution (erasure medium), they retain the capacity of rapid recapitulation for 80 min, then completely lose this capacity in a single, synchronous step referred to as the "erasure event." The erasure event sets in motion a program of dedifferentiation during which cells lose developmentally acquired characteristics at different times. The erasure event is inhibited by the addition of 10(-4) M cAMP to erasure medium. The synthesis of 33 growth-associated polypeptides, the synthesis of 53 development-associated polypeptides, and the level of 2 development-associated RNAs have been monitored during the erasure program and in cultures inhibited from erasing by the addition of 10(-4) M cAMP. Growth-associated polypeptides begin to be resynthesized and development-associated polypeptides exhibit dramatic decreases in rate of synthesis at different times throughout the first 240 min in erasure medium. Inhibiting the erasure event with cAMP has no major effect in the resynthesis of the majority of growth-associated polypeptides. Only one growth-associated polypeptide, V28, is completely inhibited by cAMP, suggesting that it may play a role in the erasure process. In contrast, inhibiting the erasure event with cAMP has a marked effect on the synthesis of development-associated polypeptides, causing a dramatic reduction in the rate at which synthesis decreases for 6 polypeptides, and completely inhibits the decrease in the synthetic rate of 8 polypeptides. The two development-associated RNAs, 16G1 and 10C3, exhibit two distinctly different patterns of loss during erasure, but in both cases cAMP added at time zero of the erasure process dramatically retards or inhibits loss. In addition, when cAMP is added just prior to the erasure event, it inhibits the erasure event and stimulates a rapid increase in the level of 16G1 RNA back to the developmental level. The level of 16G1 RNA then remains at this level for at least 400 min. When cAMP is added after the erasure event, it causes a low, transient increase in the level of 16G1 RNA. These results are considered both in relation to the program of erasure, and in relation to the role of cAMP in the expression of developmental genes during the forward program of development. 相似文献
9.
Divisional activity, intrusive growth of the cell wall and loss of fusiform initials have been studied in Holoptelea integrifolia. The dimensional changes in relation to mean length, length frequency, mean width and length variation in relation to fibre length have also been analysed. 相似文献
10.
This paper examines the effects of the 1984 drought upon household wealth differences in a community of Ariaal pastoralists of northern Kenya. The database consists of 1985 post-drought livestock counts and informants' statements of species-specific drought loss, compared to 1976 livestock counts on the same 38 households. The analysis confirms the hypothesis that the drought resulted in increased household wealth inequalities. It is suggested that the combination of differential herd growth, differential participation in the cash market, and differential loss to the drought has contributed to a polarization within Ariaal of rich and poor, resulting in rural proletarianization and urban migration. 相似文献