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A study in this issue of Cell illustrates the power of applying genomic approaches with model systems to characterize the biological activity of small molecules and to identify their cellular targets, which can clarify the mode of action of human therapeutics. 相似文献
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A new siliconized-glass fiber as support for protein-chemical analysis of electroblotted proteins 总被引:44,自引:0,他引:44
A new hydrophobic glass-fiber support is presented, which is well suited to the electrophoretic transfer of proteins from polyacrylamide gels and subsequent protein-chemical analysis. Modified glass-fiber sheets are easily prepared by chemical reaction of the surface with poly(methyl-3,3,3-trifluoropropylsiloxane) in trifluoroacetic acid. The modification is stable during electroblotting, amino acid sequence analysis and hydrolysis. The siliconized glass fiber exhibits a high protein-binding capacity, allows the application of well-established staining procedures, and does not interfere with the analytical methods of modern protein chemistry at the low picomole level. Samples separated by electrophoresis and immobilized on hydrophobic supports fail to exhibit any detectable contamination in amino acid sequence analysis hence allowing the high performance of the available protein-chemical methods to be exploited. 相似文献
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Background
There has been paid more and more attention to supervised classification models in the area of predicting drug-target interactions (DTIs). However, in terms of classification, unavoidable missing DTIs in data would cause three issues which have not yet been addressed appropriately by former approaches. Directly labeled as negatives (non-DTIs), missing DTIs increase the confusion of positives (DTIs) and negatives, aggravate the imbalance between few positives and many negatives, and are usually discriminated as highly-scored false positives, which influence the existing measures sharply.Results
Under the framework of local classification model (LCM), this work focuses on the scenario of predicting how possibly a new drug interacts with known targets. To address the first two issues, two strategies, Spy and Super-target, are introduced accordingly and further integrated to form a two-layer LCM. In the bottom layer, Spy-based local classifiers for protein targets are built by positives, as well as reliable negatives identified among unlabeled drug-target pairs. In the top layer, regular local classifiers specific to super-targets are built with more positives generated by grouping similar targets and their interactions. Furthermore, to handle the third issue, an additional performance measure, Coverage, is presented for assessing DTI prediction. The experiments based on benchmark datasets are finally performed under five-fold cross validation of drugs to evaluate this approach. The main findings are concluded as follows. (1) Both two individual strategies and their combination are effective to missing DTIs, and the combination wins the best. (2) Having the advantages of less confusing decision boundary at the bottom layer and less biased decision boundary at the top layer, our two-layer LCM outperforms two former approaches. (3) Coverage is more robust to missing interactions than other measures and is able to evaluate how far one needs to go down the list of targets to cover all the proper targets of a drug.Conclusions
Proposing two strategies and one performance measure, this work has addressed the issues derived from missing interactions, which cause confusing and biased decision boundaries in classifiers, as well as the inappropriate measure of predicting performance, in the scenario of predicting interactions between new drugs and known targets.6.
Current strategies for identifying and validating targets for new treatment-shortening drugs for TB 总被引:2,自引:0,他引:2
There is an urgent need for new drugs to treat tuberculosis. During the last forty years the only drugs to have been developed are variations on existing ones, but new drug candidates must offer improvements over existing agents. In particular, we require new drugs having novel mechanisms of action that are active against drug-resistant strains and also kill persistent bacilli, thus shortening the length of chemotherapy. Recent advances in our understanding of the biology of Mycobacterium tuberculosis, in particularly the availability of the genome sequence coupled with development of new genetic tools, have greatly contributed to the discovery of potential drug targets for new antituberculars. However, although many potential new drug targets have been identified, greater effort is required in target validation to show properly that they are essential for bacterial growth and survival. In this review, the current drug development pipeline and the strategies employed to identify and validate novel tuberculosis drug targets are presented. 相似文献
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In-depth analysis of molecular regulatory networks in cancer holds the promise of improved knowledge of the pathophysiology of tumor cells so that it will become possible to design a detailed molecular tumor taxonomy. This knowledge will also offer new opportunities for the identification and validation of key molecular tumor targets to be exploited for novel therapeutic approaches. Some signaling proteins have already been identified as such, e.g. c-Myc, Cyclin D1, Bcl-XL, kinases and some nuclear receptors. This has led to the successful development of a few function-modulatory drugs (Glivec, SERM, Iressa), providing proof-of-principle of the validity of this approach. Further developments are likely to derive from "-omic" approaches, aimed at the understanding of signaling networks and of the mechanism of action of newfound lead molecules. High-throughput screening of small drug-like molecules from combinatorial chemical libraries or from microbial extracts will identify novel, "intelligent" drug candidates. An additional medicinal chemistry strategy (via 40-50 unit rosary-bead chains) has the potential to be much more effective than small molecules in interfering with protein-protein interactions. This may lead to considerably higher selectivity and effectiveness compared with historical approaches in drug discovery. 相似文献
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Wang J Song JJ Franklin MC Kamtekar S Im YJ Rho SH Seong IS Lee CS Chung CH Eom SH 《Structure (London, England : 1993)》2001,9(2):177-184
BACKGROUND: The bacterial heat shock locus HslU ATPase and HslV peptidase together form an ATP-dependent HslVU protease. Bacterial HslVU is a homolog of the eukaryotic 26S proteasome. Crystallographic studies of HslVU should provide an understanding of ATP-dependent protein unfolding, translocation, and proteolysis by this and other ATP-dependent proteases. RESULTS: We present a 3.0 A resolution crystal structure of HslVU with an HslU hexamer bound at one end of an HslV dodecamer. The structure shows that the central pores of the ATPase and peptidase are next to each other and aligned. The central pore of HslU consists of a GYVG motif, which is conserved among protease-associated ATPases. The binding of one HslU hexamer to one end of an HslV dodecamer in the 3.0 A resolution structure opens both HslV central pores and induces asymmetric changes in HslV. CONCLUSIONS: Analysis of nucleotide binding induced conformational changes in the current and previous HslU structures suggests a protein unfolding-coupled translocation mechanism. In this mechanism, unfolded polypeptides are threaded through the aligned pores of the ATPase and peptidase and translocated into the peptidase central chamber. 相似文献
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Lazear E Whitbeck JC Ponce-de-Leon M Cairns TM Willis SH Zuo Y Krummenacher C Cohen GH Eisenberg RJ 《Journal of virology》2012,86(3):1563-1576
As the receptor-binding protein of herpes simplex virus (HSV), gD plays an essential role in virus entry. In its native state, the last 56 amino acids of the ectodomain C terminus (C-term) occlude binding to its receptors, herpesvirus entry mediator (HVEM) and nectin-1. Although it is clear that movement of the C-term must occur to permit receptor binding, we believe that this conformational change is also a key event for triggering later steps leading to fusion. Specifically, gD mutants containing disulfide bonds that constrain the C-term are deficient in their ability to trigger fusion following receptor binding. In this report, we show that two newly made monoclonal antibodies (MAbs), MC2 and MC5, have virus-neutralizing activity but do not block binding of gD to either receptor. In contrast, all previously characterized neutralizing anti-gD MAbs block binding of gD to a receptor(s). Interestingly, instead of blocking receptor binding, MC2 significantly enhances the affinity of gD for both receptors. Several nonneutralizing MAbs (MC4, MC10, and MC14) also enhanced gD-receptor binding. While MC2 and MC5 recognized different epitopes on the core of gD, these nonneutralizing MAbs recognized the gD C-term. Both the neutralizing capacity and rate of neutralization of virus by MC2 are uniquely enhanced when MC2 is combined with MAb MC4, MC10, or MC14. We suggest that MC2 and MC5 prevent gD from performing a function that triggers later steps leading to fusion and that the epitope for MC2 is normally occluded by the C-term of the gD ectodomain. 相似文献
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Dimeric effectors caspase 3 and caspase 7 are activated by initiator caspase processing. In this study, we report the crystal structures of effector caspase 6 (CASP6) zymogen and N-Acetyl-Val-Glu-Ile-Asp-al-inhibited CASP6. Both of these forms of CASP6 have a dimeric structure, and in CASP6 zymogen the intersubunit cleavage site (190)TEVD(193) is well structured and inserts into the active site. This positions residue Asp 193 to be easily attacked by the catalytic residue Cys 163. We demonstrate biochemically that intramolecular cleavage at Asp 193 is a prerequisite for CASP6 self-activation and that this activation mechanism is dependent on the length of the L2 loop. Our results indicate that CASP6 can be activated and regulated through intramolecular self-cleavage. 相似文献
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Combinations of anticancer drugs and immunotherapy 总被引:3,自引:0,他引:3
Mitchell MS 《Cancer immunology, immunotherapy : CII》2003,52(11):686-692
Immunotherapy (biological therapy) comprises such things as active specific immunotherapy ("cancer vaccines"), nonspecific immunostimulation with cytokines, and the inhibition of suppressor influences exerted or elicited by the tumor. Just as cancer chemotherapy began with the use of single agents and evolved into combination therapy, so immunotherapeutic agents have been combined with each other and with chemotherapy. The alkylating agent cyclophosphamide (Cytoxan; CYC) has been used for many years to inhibit tumor-derived suppressor influences in rodents, and has been exploited for the same use in humans. Combinations of CYC and cancer vaccines such as autologous tumor cells, Melacine, large multivalent immunogen (LMI), and Theratope have been tested with some success in humans for more than a decade. In this use, the CYC is a biological response modifier rather than an antitumor agent, intended to inhibit suppressor influences. CYC and low- to moderate-dose IL-2 has also been a useful regimen in treating human melanomas. IL-2 is itself a useful component of combination immunotherapy, such as with melanoma peptide vaccines, or with interferon -2b, (IFN-), as a dual combination or part of a biochemotherapy regimen. Several different combinations of drugs and biological agents have been used as biochemotherapy for melanoma, but although there are higher response (regression) rates the long-range survival benefits have been marginal, not justifying the severe toxicity. Combinations of 5-fluorouracil (5-FU) and IFN- or levamisole have had efficacy in colon and head and neck cancers, but here the biological agents have been biochemical modulators, not immunotherapy. Although experience with combinations of monoclonal antibodies and chemotherapy has been limited, it appears that trastuzumab (Herceptin) potentiates antitumor therapy in breast cancer but also increases the cardiotoxicity of those regimens.This article forms part of the Symposium in Writing on "Cellular immunity for cancer chemoimmunotherapy" in Volume 52 (2003) 相似文献
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Fms1 is a rate-limiting enzyme for the biosynthesis of pantothenic acid in yeast. Fms1 has polyamine oxidase (PAO) activity, which converts spermine into spermidine and 3-aminopropanal. The 3-aminopropanal is further oxidized to produce beta-alanine, which is necessary for the biosynthesis of pantothenic acid. The crystal structures of Fms1 and its complex with the substrate spermine have been determined using the single-wavelength anomalous diffraction (SAD) phasing method. Fms1 consists of an FAD-binding domain, with Rossmann fold topology, and a substrate-binding domain. The active site is a tunnel located at the interface of the two domains. The substrate spermine binds to the active site mainly via hydrogen bonds and hydrophobic interactions. In the complex, C11 but not C9 of spermine is close enough to the catalytic site (N5 of FAD) to be oxidized. Therefore, the products are spermidine and 3-aminopropanal, rather than 3-(aminopropyl) 4-aminobutyraldehyde and 1,3-diaminoprone. 相似文献
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Specific targets for antiviral drugs. 总被引:7,自引:0,他引:7
E De Clercq 《The Biochemical journal》1982,205(1):1-13
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New targets for anti-inflammatory drugs. 总被引:6,自引:0,他引:6
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Ginger CD 《Parasitology today (Personal ed.)》1991,7(10):262-264
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Leucyl-tRNA synthetase (LeuRS) specifically recognizes the characteristic long variable arm and the discriminator base, A73, of tRNA(Leu) in archaea and eukarya. The LeuRS 'editing domain' hydrolyzes misformed noncognate aminoacyl-tRNA. Here we report the crystal structure of the archaeal Pyrococcus horikoshii LeuRS-tRNA(Leu) complex. The protruding C-terminal domain of LeuRS specifically recognizes the bases at the tip of the long variable arm. The editing domain swings from its tRNA-free position to avoid clashing with the tRNA. Consequently the tRNA CCA end can bend and reach the aminoacylation active site. The tRNA 3' region assumes two distinct conformations that allow A73 to be specifically recognized in different ways. One conformation is the canonical 'aminoacylation state.' The other conformation seems to be the 'intermediate state,' where the misaminoacylated 3' end has partially relocated to the editing domain. 相似文献
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N Ikemoto H S Kim M Kanazaki Y Ueno S Shuto A Matsuda Y Wataya 《Nucleic acids symposium series》1999,(42):89-90
We investigated about targeting for new antimalarial drugs using antisense (AS) oligodeoxynucleotides (ODNs). Synthetic nuclease-resistant ODNs (phosphorothioate (PS) ODNs and ODNs containing 4'alpha-C-(2-aminoethyl)thymidines (4'-amino ODNs)) which target mitochondrial succinate dehydrogenase (SDH) iron-sulfur subunit (IP), had antimalarial activity (EC50; about 1.0 microM). Furthermore we showed that intra-parasitic SDH IP mRNA levels, which were detected using quantitative RT-PCR assay, were decreased 13% of control after the 24 h expose to SDH IP AS. From the results, we conclude that SDH has potential as the target for novel antimalarials, and AS ODNs is effective for search and assessment of targets for new antimalarial drugs. 相似文献