共查询到20条相似文献,搜索用时 31 毫秒
1.
Intracellular signalling molecules form pathways inside the cell. These pathways carry a signal to target proteins which results
in cellular responses. We consider a spherical cell with two internal compartments containing localized activating enzymes
where as deactivating enzymes are spread uniformly through out the cytosol. Two diffusible signalling molecules are activated
at the compartments and later deactivated in the cytosol due to deactivating enzymes. The two signalling molecules are a single
link in a cascade reaction and form a self regulated dynamical system involving positive and negative feedback. Using matched
asymptotic expansions we obtain approximate solutions of the steady state diffusion equation with a linear decay rate. We
obtain three-dimensional concentration profiles for the signalling molecules. We also investigate an extension of the above
system which has multiple cascade reactions occurring between multiple signalling molecules. Numerically, we show that the
speed of the signal is an increasing function of the number of links in the cascade. 相似文献
2.
The last decade has witnessed many exciting scientific publications associated with site-selective reactions of small chemical molecules with imperfectly matched DNA. Typical examples are carbodiimide, hydroxylamine, potassium permanganate, osmium tetroxide, chemical tagging probes, biotinylated, chemiluminescent and fluorescent probes, and all of them selectively react with imperfectly matched DNA. More recently, some therapeutic agents including DNA intercalating drugs and groove binders have been found to promote the in vivo repair system to recognize and repair the mismatch more effectively. The results have established a novel method for detection of mismatches. Development of new chemical reactions for detection of imperfectly matched DNA and mutations is a rapidly growing field and has attracted significant interest of scientists from both chemical and biological fields and it is the main focus of this review. 相似文献
3.
David R. Eyre Stephen Apon Jiann-Jiu Wu Lowell H. Ericsson Kenneth A. Walsh 《FEBS letters》1987,220(2):337-341
A major site of pyridinoline cross-linking in bovine type IX collagen was traced to a tryptic peptide derived from one of the molecule's HMW chains. This peptide gave two amino acid sequences (in 2/1 ratio) consistent with it being a three-chained structure. The major sequence matched exactly that of the C-telopeptide of type II collagen from the same tissue. A second HMW chain that contained pyridinoline cross-links also gave two amino-terminal sequences, one from its own amino terminus, the other matching exactly the N-telopeptide cross-linking sequence of type II collagen. We conclude that type IX collagen molecules are covalently cross-linked in cartilage to molecules of type II collagen, probably at fibril surfaces. 相似文献
4.
Cross-helix separation of tropomyosin molecules in acto-tropomyosin as determined by neutron scattering.
下载免费PDF全文
![点击此处可从《Biophysical journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The cross-helix separation of Tm molecules in acto-tropomyosin has been determined using neutron scattering. Deuterated Dictyostelium discoideum actin was density matched in a 93% D2O buffer so that effectively only the protonated tropomyosin was "visible" to neutrons. Analysis of the solution scattering pattern in the region of the first oscillation yielded a value for the cross-helix separation of 7.9 +/- 0.3 nm. The implications of this value for the mechanism of the regulation of muscle contraction are discussed in light of recent results by others. 相似文献
5.
The ventral, postsynaptic membranes of the electroplaques of Narcine were examined for structures corresponding in location, numbers, position and form with nicotinic acetylcholine receptor-channel molecules. Electron micrographs of conventionally fixed material showed that the thickened outer lamina of these membranes contained about 6100 stained structures/μm2 ; and calculations from this packing density and the estimated area of postsynaptic membranes/g tissue yielded a total number of structures within a factor of two of the number of receptor molecules/g determined from the binding of alpha-bungarotoxin. Examination of tissue prepared with a tannic acid/glutaraldehyde fixative revealed that the structures were uniform in character, cylindrical in shape, transmembrane in position, and that each contained a central core. Their diameter matched that of isolated receptor molecules, and their size can account for most of the receptor protein. We conclude that these receptor molecules are largely intramembranous, cylindrical and exhibit transmembrane pores. 相似文献
6.
Attila Molnar rew Bassett Eva Thuenemann Frank Schwach Shantanu Karkare Stephan Ossowski Detlef Weigel David Baulcombe 《The Plant journal : for cell and molecular biology》2009,58(1):165-174
MicroRNAs (miRNAs) are small RNAs, 21 to 22 nucleotides long, with important regulatory roles. They are processed from longer RNA molecules with imperfectly matched foldback regions and they function in modulating the stability and translation of mRNA. Recently, we and others have demonstrated that the unicellular alga Chlamydomonas reinhardtii , like diverse multicellular organisms, contains miRNAs. These RNAs resemble the miRNAs of land plants in that they direct site-specific cleavage of target mRNA with miRNA-complementary motifs and, presumably, act as regulatory molecules in growth and development. Utilizing these findings we have developed a novel artificial miRNA system based on ligation of DNA oligonucleotides that can be used for specific high-throughput gene silencing in green algae. 相似文献
7.
We consider Bayesian methodology for comparing two or more unlabeled point sets. Application of the technique to a set of steroid molecules illustrates its potential utility involving the comparison of molecules in chemoinformatics and bioinformatics. We initially match a pair of molecules, where one molecule is regarded as random and the other fixed. A type of mixture model is proposed for the point set coordinates, and the parameters of the distribution are a labeling matrix (indicating which pairs of points match) and a concentration parameter. An important property of the likelihood is that it is invariant under rotations and translations of the data. Bayesian inference for the parameters is carried out using Markov chain Monte Carlo simulation, and it is demonstrated that the procedure works well on the steroid data. The posterior distribution is difficult to simulate from, due to multiple local modes, and we also use additional data (partial charges on atoms) to help with this task. An approximation is considered for speeding up the simulation algorithm, and the approximating fast algorithm leads to essentially identical inference to that under the exact method for our data. Extensions to multiple molecule alignment are also introduced, and an algorithm is described which also works well on the steroid data set. After all the steroid molecules have been matched, exploratory data analysis is carried out to examine which molecules are similar. Also, further Bayesian inference for the multiple alignment problem is considered. 相似文献
8.
Bitto E Bingman CA Kondrashov DA McCoy JG Bannen RM Wesenberg GE Phillips GN 《Proteins》2008,70(1):93-104
Soluble N-ethylmaleimide-sensitive factor attachment protein gamma (gamma-SNAP) is a member of an eukaryotic protein family involved in intracellular membrane trafficking. The X-ray structure of Brachydanio rerio gamma-SNAP was determined to 2.6 A and revealed an all-helical protein comprised of an extended twisted-sheet of helical hairpins with a helical-bundle domain on its carboxy-terminal end. Structural and conformational differences between multiple observed gamma-SNAP molecules and Sec17, a SNAP family protein from yeast, are analyzed. Conformational variation in gamma-SNAP molecules is matched with great precision by the two lowest frequency normal modes of the structure. Comparison of the lowest-frequency modes from gamma-SNAP and Sec17 indicated that the structures share preferred directions of flexibility, corresponding to bending and twisting of the twisted sheet motif. We discuss possible consequences related to the flexibility of the SNAP proteins for the mechanism of the 20S complex disassembly during the SNAP receptors recycling. 相似文献
9.
Kanti V. Mardia Vysaul B. Nyirongo Christopher J. Fallaize Stuart Barber Richard M. Jackson 《Biometrics》2011,67(2):611-619
Summary One of the key ingredients in drug discovery is the derivation of conceptual templates called pharmacophores. A pharmacophore model characterizes the physicochemical properties common to all active molecules, called ligands, bound to a particular protein receptor, together with their relative spatial arrangement. Motivated by this important application, we develop a Bayesian hierarchical model for the derivation of pharmacophore templates from multiple configurations of point sets, partially labeled by the atom type of each point. The model is implemented through a multistage template hunting algorithm that produces a series of templates that capture the geometrical relationship of atoms matched across multiple configurations. Chemical information is incorporated by distinguishing between atoms of different elements, whereby different elements are less likely to be matched than atoms of the same element. We illustrate our method through examples of deriving templates from sets of ligands that all bind structurally related protein active sites and show that the model is able to retrieve the key pharmacophore features in two test cases. 相似文献
10.
Phenotype frequencies of autosomal minor histocompatibility antigens display significant differences among populations 总被引:1,自引:0,他引:1
下载免费PDF全文
![点击此处可从《PLoS genetics》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Spierings E Hendriks M Absi L Canossi A Chhaya S Crowley J Dolstra H Eliaou JF Ellis T Enczmann J Fasano ME Gervais T Gorodezky C Kircher B Laurin D Leffell MS Loiseau P Malkki M Markiewicz M Martinetti M Maruya E Mehra N Oguz F Oudshoorn M Pereira N Rani R Sergeant R Thomson J Tran TH Turpeinen H Yang KL Zunec R Carrington M de Knijff P Goulmy E 《PLoS genetics》2007,3(6):e103
Minor histocompatibility (H) antigens are allogeneic target molecules having significant roles in alloimmune responses after human leukocyte antigen–matched solid organ and stem cell transplantation (SCT). Minor H antigens are instrumental in the processes of transplant rejection, graft-versus-host disease, and in the curative graft-versus-tumor effect of SCT. The latter characteristic enabled the current application of selected minor H antigens in clinical immunotherapeutic SCT protocols. No information exists on the global phenotypic distribution of the currently identified minor H antigens. Therefore, an estimation of their overall impact in human leukocyte antigen–matched solid organ and SCT in the major ethnic populations is still lacking. For the first time, a worldwide phenotype frequency analysis of ten autosomal minor H antigens was executed by 31 laboratories and comprised 2,685 randomly selected individuals from six major ethnic populations. Significant differences in minor H antigen frequencies were observed between the ethnic populations, some of which appeared to be geographically correlated. 相似文献
11.
All docking methods employ some sort of heuristic to orient the ligand molecules into the binding site of the target structure. An automated method, MCSS2SPTS, for generating chemically labeled site points for docking is presented. MCSS2SPTS employs the program Multiple Copy Simultaneous Search (MCSS) to determine target-based theoretical pharmacophores. More specifically, chemically labeled site points are automatically extracted from selected low-energy functional-group minima and clustered together. These pharmacophoric site points can then be directly matched to the pharmacophoric features of database molecules with the use of either DOCK or PhDOCK to place the small molecules into the binding site. Several examples of the ability of MCSS2SPTS to reproduce the three-dimensional pharmacophoric features of ligands from known ligand-protein complex structures are discussed. In addition, a site-point set calculated for one human immunodeficiency virus 1 (HIV1) protease structure is used with PhDOCK to dock a set of HIV1 protease ligands; the docked poses are compared to the corresponding complex structures of the ligands. Finally, the use of an MCSS2SPTS-derived site-point set for acyl carrier protein synthase is compared to the use of atomic positions from a bound ligand as site points for a large-scale DOCK search. In general, MCSS2SPTS-generated site points focus the search on the more relevant areas and thereby allow for more effective sampling of the target site. 相似文献
12.
OKT4+ cytotoxic T cells can lyse targets via class I molecules and can be blocked by monoclonal antibody against T4 molecules 总被引:2,自引:0,他引:2
Human cytotoxic T lymphocytes (CTL) have been shown to recognize either class I or class II major histocompatibility (MHC) products. This recognition has been correlated with the expression of OKT antigens on the surface of the CTL. Thus, OKT4+ CTL have been shown to be reactive with class II products, whereas OKT8+ effectors recognize class I molecules. In this study, responder cells were separated according to their OKT4 or OKT8 cell surface phenotype on a fluorescence-activated cell sorter (FACS). The OKT4+ subsets were stimulated with an LCL mutant that did not express DR and MB/MT but did express SB and class I antigens. After 7 days in culture, the activated subsets were tested on a panel of class I matched or mismatched targets. The cytotoxicity observed could be correlated with the presence of matched class I antigens. In addition, monoclonal antibody (MCA) W6/32, directed at a monomorphic determinant on HLA-A and -B molecules, blocked lysis. Furthermore, six OKT4+ CTL clones were derived from the OKT4+ bulk cultures; three clones were found to be directed at class I molecules whereas the other three recognized class II determinants. The ability of these clones to lyse their relevant targets was blocked by OKT4 MCA, raising questions as to the role of the T4 molecule in antigen class-specific CTL recognition. 相似文献
13.
Where structural similarities between molecular ligands are suspected in competitive binding, these similarities may be represented by a set of correspondences between analogous ligand points in the two molecules. This paper describes an algorithm which searches through all possible sets of this form, to find the one which gives the best geometric fit between matched points. Two parameters are supplied to the algorithm, giving the number of correspondences required and the tolerance permitted in the fit. A tree-search technique is used, and methods are described which prune the tree and thus limit the search. The marine neurotoxins, saxitoxin and tetrodotoxin, are used to test a computer implementation of the procedure. 相似文献
14.
Aqueous solubility is an important biopharmaceutical property in drug discovery and development. Although it has been studied for decades, the impact on solubility by the substructures (or fragments) of compounds are still not fully understood and characterized. This study aims to obtain fragment-solubility relationships using matched molecular pairs, and to provide further insight and suggestions for chemists on structural modifications to improve solubility profiles of drug-like molecules. A set of 2794 compounds with measured intrinsic aqueous solubility (logS) was fragmented into rings, linkers, and R groups using a controlled hierarchical fragmentation method. Then matched molecular pairs that differ by only one chemical transformation (i.e., addition or substitution of fragments) were identified and analyzed. The difference in solubility for each matched molecular pair was calculated, and the impact of the corresponding chemical transformation on solubility was investigated. The final product of this study was a fragment-solubility knowledgebase containing relative contributions to solubility of various medicinal chemistry design elements (R-groups, linkers, and rings). Structural modifications that might improve solubility profiles, that is, addition/deletion/substitution of fragments, could be derived from this knowledgebase. This knowledgebase could be used as an expert tool in lead optimization to improve solubility profiles of compounds, and the analysis method could be applied to study other biological and ADMET properties of organic compounds. 相似文献
15.
16.
This article presents a general statistical mechanical approach to describe self-folding together with the hybridization between a pair of finite length DNA or RNA molecules. The model takes into account the entire ensemble of single- and double-stranded species in solution and their mole fractions at different temperatures. The folding and hybridization models deal with matched pairs, mismatches, symmetric and asymmetric interior loops, bulges, and single-base stacking that might exist at duplex ends or at the ends of helices. All possible conformations of the single- and double-stranded species are explored. Only intermolecular basepairs are considered in duplexes at this stage.In particular we focus on the role of stacking between neighboring nucleotide residues of single unfolded strands as an important source of enthalpy change on helix formation which has not been modeled computationally thus far. Changes in the states of the single strands with temperature are shown to lead to a larger heat effect at higher temperature. An important consequence of this is that predictions of enthalpies, which are based on databases of nearest-neighbor energy parameters determined for molecules or duplexes with lower melting temperatures compared with the melting temperatures of the oligos for which they are used as a predictive tool, will be underestimated. 相似文献
17.
Approaches which start from a study of the interaction of very simple molecules (fragments) with the protein target are proving to be valuable additions to drug design. Fragment-based screening allows the complementarity between a protein active site and drug-like molecules to be rapidly and effectively explored, using structural methods. Recent improvements in the intensities of laboratory X-ray sources permits the collection of greater amounts of high-quality diffraction data and have been matched by developments in automation, crystallisation and data analysis. Developments in NMR screening, including the use of cryogenically cooled NMR probes and (19)F-containing reporter molecules have expanded the scope of this technique, while increasing the availability of binding site and quantitative affinity data for the fragments. Application of these methods has led to a greater knowledge of the chemical variety, structural features and energetics of protein-fragment interactions. While fragment-based screening has already been shown to reduce the timescales of the drug discovery process, a more detailed characterisation of fragment screening hits can reveal unexpected similarities between fragment chemotypes and protein active sites leading to improved understanding of the pharmacophores and the re-use of this information against other protein targets. 相似文献
18.
19.
20.
Small non-coding RNAs play important roles in regulating cell functions by controlling mRNA turnover and translational repression
in eukaryotic cells. Here we isolated 162 endogenous small RNA molecules from Oryza sativa, which ranged from 16 to 35 nt in length. Further analysis indicated that they represented a diversity of small RNA molecules,
including 17 microRNAs (miRNAs), 30 tiny non-coding RNAs (tncRNAs) and 20 repeat-associated small interfering RNAs (rasiRNAs).
Among 17 miRNAs, 13 were novel miRNA candidates and their potential targets were important regulatory genes in the rice genome.
We also found that a cluster of small RNAs, including many rasiRNAs, matched to a nuclear DNA fragment that evolutionarily
derived from chloroplast. These results demonstrate clearly the existence of distinct types of small RNAs in rice and further
suggest that small RNAs may control gene regulation through diverse mechanisms. 相似文献