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61.
Yoichi Nishiya Kenji Shibata Seiji Saito Keiichi Yano Chitose Oneyama Hirofumi Nakano Sreenath V. Sharma 《Analytical biochemistry》2009,385(2):314-320
Identification of drug targets is a key step in the development of novel pharmaceuticals. To this end, chemical probes or affinity matrices are often used, requiring substantial structure–activity relationship (SAR) studies. Here we report on the development of a novel technique for drug–target identification from total cellular lysate conducted independently of SAR information. This technique relies on binding of a drug to its target inducing a conformational change in target protein, thereby altering its susceptibility to proteolysis and resulting in specific degradation in some cases or in protection of target protein in others. As proof of concept, three drugs with identified targets were used. First, incubation of cellular lysates with okadaic acid elicited a specific protective effect on its target, protein phosphatase 2A catalytic subunit. Second, specific protection from exogenous protease of FKBP12 by FK506 and Hsp90 fragments by radicicol were observed. We then used the method to validate the targets of UCS15A, an Src signaling inhibitor. UCS15A induced proteolysis of a number of proteins, one of which was identified as Sam68. These studies suggest that the technology may be generally useful for identification and validation of drug targets. 相似文献
62.
Makoto Yanagihara Masako Kawasaki Hiroshi Ishizaki Kazushi Anzawa Shun-ichi Udagawa Takashi Mochizuki Yukio Sato Nobuyuki Tachikawa Hiroyoshi Hanakawa 《Mycoscience》2010,51(3):224-233
A 74-year-old healthy Japanese man had noticed an itchy lesion with two tiny thick brown scales on the fourth interdigital
web of his right foot 3 months earlier. The brown fungus isolated from the scales had demonstrated brown, ellipsoidal, obovoid
or clavate, 3-septate conidia. Morphologically, the fungus was identified as Curvularia sp., and was differentiated from other human pathogenic species of the genus, such as C. lunata, C. pallescens, C. trifolii, C. clavata, and C. brachyspora, by molecular analysis based on the DNA sequence data. The fungus grows well on keratotic materials (hairs, nails, and callus),
which indicates that it might have the ability to infect the skin surface. 相似文献
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64.
Gallego-Bartolomé J Kami C Fankhauser C Alabadí D Blázquez MA 《Plant physiology》2011,156(4):1819-1825
Plants orient their growth depending on directional stimuli such as light and gravity, in a process known as tropic response. Tropisms result from asymmetrical accumulation of auxin across the responding organ relative to the direction of the stimulus, which causes differential growth rates on both sides of the organ. Here, we show that gibberellins (GAs) attenuate the gravitropic reorientation of stimulated hypocotyls of dark-grown Arabidopsis (Arabidopsis thaliana) seedlings. We show that the modulation occurs through induction of the expression of the negative regulator of auxin signaling INDOLE-3-ACETIC ACID INDUCIBLE19/MASSUGU2. The biological significance of this regulatory mechanism involving GAs and auxin seems to be the maintenance of a high degree of flexibility in tropic responses. This notion is further supported by observations that GA-deficient seedlings showed a much lower variance in the response to gravity compared to wild-type seedlings and that the attenuation of gravitropism by GAs resulted in an increased phototropic response. This suggests that the interplay between auxin and GAs may be particularly important for plant orientation under competing tropic stimuli. 相似文献
65.
Peroxisomes are degraded by a selective type of autophagy known as pexophagy. Several different types of pexophagy have been reported in mammalian cells. However, the mechanisms underlying how peroxisomes are recognized by autophagy-related machinery remain elusive. PEX3 is a peroxisomal membrane protein (PMP) that functions in the import of PMPs into the peroxisomal membrane and has been shown to interact with pexophagic receptor proteins during pexophagy in yeast. Thus, PEX3 is important not only for peroxisome biogenesis, but also for peroxisome degradation. However, whether PEX3 is involved in the degradation of peroxisomes in mammalian cells is unclear. Here, we report that high levels of PEX3 expression induce pexophagy. In PEX3-loaded cells, peroxisomes are ubiquitinated, clustered, and degraded in lysosomes. Peroxisome targeting of PEX3 is essential for the initial step of this degradation pathway. The degradation of peroxisomes is inhibited by treatment with autophagy inhibitors or siRNA against NBR1, which encodes an autophagic receptor protein. These results indicate that ubiquitin- and NBR1-mediated pexophagy is induced by increased expression of PEX3 in mammalian cells. In addition, another autophagic receptor protein, SQSTM1/p62, is required only for the clustering of peroxisomes. Expression of a PEX3 mutant with substitution of all lysine and cysteine residues by arginine and alanine, respectively, also induces peroxisome ubiquitination and degradation, hence suggesting that ubiquitination of PEX3 is dispensable for pexophagy and an endogenous, unidentified peroxisomal protein is ubiquitinated on the peroxisomal membrane. 相似文献
66.
Ayumi Miyake Tatsuya Chitose Eriko Kamei Atsuko Murakami Yoshiaki Nakayama Morichika Konishi Nobuyuki Itoh 《PloS one》2014,9(10)
Fibroblast growth factor (Fgf) signaling plays crucial roles in various developmental processes including those in the brain. We examined the role of Fgf16 in the formation of the zebrafish brain. The knockdown of fgf16 decreased cell proliferation in the forebrain and midbrain. fgf16 was also essential for development of the ventral telencephalon and diencephalon, whereas fgf16 was not required for dorsoventral patterning in the midbrain. fgf16 was additionally required for the specification and differentiation of γ–aminobutyric acid (GABA)ergic interneurons and oligodendrocytes, but not for those of glutamatergic neurons in the forebrain. Cross talk between Fgf and Hedgehog (Hh) signaling was critical for the specification of GABAergic interneurons and oligodendrocytes. The expression of fgf16 in the forebrain was down-regulated by the inhibition of Hh and Fgf19 signaling, but not by that of Fgf3/Fgf8 signaling. The fgf16 morphant phenotype was similar to that of the fgf19 morphant and embryos blocked Hh signaling. The results of the present study indicate that Fgf16 signaling, which is regulated by the downstream pathways of Hh-Fgf19 in the forebrain, is involved in forebrain development. 相似文献
67.
Yuzuru Itoh Markus J. Bröcker Shun-ichi Sekine Dieter Söll Shigeyuki Yokoyama 《Journal of molecular biology》2014
The 21st amino acid, selenocysteine (Sec), is incorporated translationally into proteins and is synthesized on its specific tRNA (tRNASec). In Bacteria, the selenocysteine synthase SelA converts Ser-tRNASec, formed by seryl-tRNA synthetase, to Sec-tRNASec. SelA, a member of the fold-type-I pyridoxal 5′-phosphate-dependent enzyme superfamily, has an exceptional homodecameric quaternary structure with a molecular mass of about 500 kDa. Our previously determined crystal structures of Aquifex aeolicus SelA complexed with tRNASec revealed that the ring-shaped decamer is composed of pentamerized SelA dimers, with two SelA dimers arranged to collaboratively interact with one Ser-tRNASec. The SelA catalytic site is close to the dimer–dimer interface, but the significance of the dimer pentamerization in the catalytic site formation remained elusive. In the present study, we examined the quaternary interactions and demonstrated their importance for SelA activity by systematic mutagenesis. Furthermore, we determined the crystal structures of “depentamerized” SelA variants with mutations at the dimer–dimer interface that prevent pentamerization. These dimeric SelA variants formed a distorted and inactivated catalytic site and confirmed that the pentamer interactions are essential for productive catalytic site formation. Intriguingly, the conformation of the non-functional active site of dimeric SelA shares structural features with other fold-type-I pyridoxal 5′-phosphate-dependent enzymes with native dimer or tetramer (dimer-of-dimers) quaternary structures. 相似文献
68.
69.
70.
Treponema phagedenis possessed the ability to induce an increase in vascular permeability (blueing) in guinea pig skin, which was exerted not only by cell-free preparations but also directly by intact cells. Cell-free preparations induced maximum blueing 0 h after sample injection, while whole cells did so after 1 h. Log dose-response curves for cell-free preparations were linear within the range of blue spots with diameters of 10–24 mm, with slopes (
) of 8.5–8.7. The vascular permeability-increasing activity was not ascribable to hyaluronidase and probably to -galactosidase; this organism did not produce any detectable hyaluronidase activity. 相似文献