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51.
Klingler O Matter H Schudok M Bajaj SP Czech J Lorenz M Nestler HP Schreuder H Wildgoose P 《Bioorganic & medicinal chemistry letters》2003,13(8):1463-1467
Selective inhibition of coagulation factor VIIa has recently gained attraction as interesting approach towards antithrombotic treatment. Using parallel synthesis supported by structure-based design and X-ray crystallography, we were able to identify a novel series of amidinophenylurea derivatives with remarkable affinity for factor VIIa. The most potent compound displays a K(i) value of 23 nM for factor VIIa. 相似文献
52.
New perspectives on the design of cytokines and growth factors 总被引:3,自引:0,他引:3
A combination of molecular modelling, conventional epitope scanning and combinatorial techniques, such as phage display and DNA shuffling, has greatly improved our understanding of ligand-receptor interactions. It has therefore been possible to develop powerful cytokine-growth factor antagonists and new designer cytokines, with altered receptor specificities or with greatly enhanced biological activity. Recently, small circular peptides that mimic or block the effects of natural cytokines and growth factors have been developed; such small peptides are likely to open new avenues in therapeutics. 相似文献
53.
Extrapore residues of the S5-S6 loop of domain 2 of the voltage-gated skeletal muscle sodium channel (rSkM1) contribute to the mu-conotoxin GIIIA binding site. 总被引:1,自引:0,他引:1
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The tetradomain voltage-gated sodium channels from rat skeletal muscle (rSkM1) and from human heart (hH1) possess different sensitivities to the 22-amino-acid peptide toxin, mu-conotoxin GIIIA (mu-CTX). rSkM1 is sensitive (IC50 = 51.4 nM) whereas hH1 is relatively resistant (IC50 = 5700 nM) to the action of the toxin, a difference in sensitivity of >100-fold. The affinity of the mu-CTX for a chimera formed from domain 1 (D1), D2, and D3 from rSkM1and D4 from hH1 (SSSH; S indicates origin of domain is skeletal muscle and H indicates origin of domain is heart) was paradoxically increased approximately fourfold relative to that of rSkM1. The source of D3 is unimportant regarding the difference in the relative affinity of rSkM1 and hH1 for mu-CTX. Binding of mu-CTX to HSSS was substantially decreased (IC50 = 1145 nM). Another chimera with a major portion of D2 deriving form hH1 showed no detectable binding of mu-CTX (IC50 > 10 microM). These data indicate that D1 and, especially, D2 play crucial roles in forming the mu-CTX receptor. Charge-neutralizing mutations in D1 and D2 (Asp384, Asp762, and Glu765) had no effect on toxin binding. However, mutations at a neutral and an anionic site (residues 728 and 730) in S5-S6/D2 of rSkM1, which are not in the putative pore region, were found to decrease significantly the mu-CTX affinity with little effect on tetrodotoxin binding (</=1.3-fold increase in affinity). Furthermore, substitution at Asp730 with cysteine and exposure to Cd2+ or methanethiosulfonate reagents had no significant effect on sodium currents, consistent with this residue not contributing to the pore. 相似文献
54.
The α-subunit cDNAs encoding voltage-sensitive sodium channels of human heart (hH1) and rat skeletal muscle (rSkM1) have
been expressed in the tsA201 mammalian cell line, in which inactivation properties appear to be normal in contrast to Xenopus oocytes. A series of rSkM1/hH1 chimeric sodium channels has been evaluated to identify the domains of the α-subunits that
are responsible for a set of electrophysiological differences between hH1 and rSkM1, namely, midpoints and slope factors of
steady-state activation and inactivation, inactivation kinetics and recovery from inactivation kinetics and their voltage-dependence.
The phenotype of chimeric channels in which each hH1 domain was successively introduced into a rSkM1 α-subunit framework confirmed
the following conclusions. (i) The D4 and or/C-ter. are responsible for the slow inactivation of hH1 sodium channels. (ii)
Concerning the other differences between rSkM1 and hH1: steady-state activation and inactivation, kinetics of recovery from
inactivation, the phenotypes are determined probably by more than one domain of the α-subunit.
Received: 20 January 1998/Revised: 19 March 1998 相似文献
55.
When working on an ongoing genome sequencing and assembly project, it is rather inconvenient when gene identifiers change from one build of the assembly to the next. The gene labelling system described here, UniqTag, addresses this common challenge. UniqTag assigns a unique identifier to each gene that is a representative k-mer, a string of length k, selected from the sequence of that gene. Unlike serial numbers, these identifiers are stable between different assemblies and annotations of the same data without requiring that previous annotations be lifted over by sequence alignment. We assign UniqTag identifiers to ten builds of the Ensembl human genome spanning eight years to demonstrate this stability. The implementation of UniqTag in Ruby and an R package are available at https://github.com/sjackman/uniqtag sjackman/uniqtag. The R package is also available from CRAN: install.packages ("uniqtag"). Supplementary material and code to reproduce it is available at https://github.com/sjackman/uniqtag-paper. 相似文献
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59.
Andrea Erlbruch Chien‐Wen Hung Joerg Seidler Katrin Borrmann Frank Gesellchen Norbert König Dieter Kübler Friedrich W. Herberg Wolf D. Lehmann Dirk Bossemeyer 《Proteomics》2010,10(16):2890-2900
An expression‐uncoupled tandem affinity purification assay is introduced which differs from the standard TAP assay by uncoupling the expression of the TAP‐bait protein from the target cells. Here, the TAP‐tagged bait protein is expressed in Escherichia coli and purified. The two concatenated purification steps of the classical TAP are performed after addition of the purified bait to brain tissue homogenates, cell and nuclear extracts. Without prior genetic manipulation of the target, upscaling, free choice of cell compartments and avoidance of expression triggered heat shock responses could be achieved in one go. By the strategy of separating bait expression from the prey protein environment numerous established, mostly tissue‐specific binding partners of the protein kinase A catalytic subunit Cβ1 were identified, including interactions in binary, ternary and quaternary complexes. In addition, the previously unknown small molecule inhibitor‐dependent interaction of Cβ1 with the cell cycle and apoptosis regulatory protein‐1 was verified. The uncoupled tandem affinity purification procedure presented here expands the application range of the in vivo TAP assay and may serve as a simple strategy for identifying cell‐ and tissue‐specific protein complexes. 相似文献
60.
Joerg Flemmig 《Journal of inorganic biochemistry》2010,104(7):759-764
The close association of the heme enzyme myeloperoxidase to phosphatidylserine epitopes on the surface of non-vital polymorphonuclear leukocytes (PMNs) and other apoptotic cells at inflammatory sites favours modifications of this phospholipid by myeloperoxidase products. As detected by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, ammonium ions inhibit in a concentration-dependent manner the hypochlorous acid-mediated formation of aldehyde and nitrile products from 1,2-dipalmitoyl-sn-glycero-3-phosphoserine (DPPS). Concomitantly, the formation of monochloramine (NH2Cl) raises with increasing NH4+ concentrations. A transchlorination from monochlorinated O-phospho-l-serine to NH4+ with the formation of NH2Cl occurs only when extraordinary high NH4+ concentrations are applied. Due to the low rate of 0.044 M− 1 s− 1 for this process, a transhalogenation reaction from transient chlorinated intermediates of the serine moiety to NH4+ can be ruled out as an important process contributing to the HOCl-mediated formation of NH2Cl. A significant formation of NH2Cl by myeloperoxidase interacting with DPPS in the presence of ammonium ions takes only place at acidic pH values around 5, a scenario that may occur in phagosomes of macrophages after the uptake of apoptotic PMNs. 相似文献