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151.
Shimamura T Shibata J Kurihara H Mita T Otsuki S Sagara T Hirai H Iwasawa Y 《Bioorganic & medicinal chemistry letters》2006,16(14):3751-3754
5-Pyrimidinyl-2-aminothiazole 1 was identified as an inhibitor of cyclin-dependent kinases (CDKs) by a screening of the Merck sample repository. The introduction of a methyl group at the C-5 or C-6 position on the pyrimidine ring, directed toward the gate keeper residue of CDK4 (Phe93), led to significant enhancement of selectivity for CDK4 over other CDKs. Compound 3 exhibited more than 300-fold selectivity for CDK4 over CDK1, 2, 5, 7, and 9. Subsequent improvements in aqueous solubility afforded compound 4, which is available for further in vivo studies and this compound inhibited pRb phosphorylation and BrdU incorporation in tumor models. 相似文献
152.
Yokoyama T Neya S Tsuneshige A Yonetani T Park SY Tame JR 《Journal of molecular biology》2006,356(3):790-801
Although detailed crystal structures of haemoglobin (Hb) provide a clear understanding of the basic allosteric mechanism of the protein, and how this in turn controls oxygen affinity, recent experiments with artificial effector molecules have shown a far greater control of oxygen binding than with natural heterotropic effectors. Contrary to the established text-book view, these non-physiological compounds are able to reduce oxygen affinity very strongly without switching the protein to the T (tense) state. In an earlier paper we showed that bezafibrate (BZF) binds to a surface pocket on the alpha subunits of R state Hb, strongly reducing the oxygen affinity of this protein conformation. Here we report the crystallisation of Hb with L35, a related compound, and show that this binds to the central cavity of both R and T state Hb. The mechanism by which L35 reduces oxygen affinity is discussed, in relation to spectroscopic studies of effector binding. 相似文献
153.
Toru Okuda Jun Kohno Noboru Kishi Yasuyuki Asai Maki Nishio Saburo Komatsubara 《Mycoscience》2000,41(3):239-253
A novel class of fungal metabolites, TMC-151, TMC-154, and TMC-171 series compounds, was found exclusively inGliocladium catenulatum, Clonostachys rosea and closely related strains. These compounds were not detected in any other fungi examined. The production spectrum of each
component was correlated to the morphology of the secondary conidiophores and the conidia. TMC-151 was limited toClonostachys rosea (formerlyG. roseum) forming navicular or reniform conidia orG. catenulatum with gray-green conidial masses, whereas TMC-154 and 171 were limited to the strains closely related toGliocladium roseum, which grew more slowly and formed more symmetrical conidia. 相似文献
154.
Aline Garcia Kozlowski Megmar Aparecida dos Santos Carneiro Márcia Alves Dias de Matos Sheila Araújo Teles Jo?o Alves Araújo Filho Koko Otsuki Ana Carolina Paulo Vicente Regina Maria Bringel Martins 《Memórias do Instituto Oswaldo Cruz》2014,109(1):118-121
Human T-cell lymphotropic virus (HTLV) may impact the clinical course of tuberculosis
(TB). Both infections are highly endemic in Brazil. The aim of this study was to
assess the prevalence of HTLV-1/2 in TB patients in Central-West Brazil and to
perform a genetic characterisation of the respective isolates. Of the 402 patients,
six (1.49%) were positive for anti-HTLV and five (1.24%; 95% confidence interval:
0.46-3.05) were infected with HTLV-1/2. Genetic characterisation demonstrated that
the four HTLV-1 isolates belonged to the Transcontinental subgroup A of the
Cosmopolitan subtype a and that the HTLV-2 isolate belonged to subtype a (HTLV-2a/c).
The prevalence of HTLV infection observed in this study is higher than that observed
in local blood donors and the HTLV-1 and 2 subtypes identified are consistent with
those circulating in Brazil. 相似文献
155.
Kanaori K Tajiri Y Tsuneshige A Ishigami I Ogura T Tajima K Neya S Yonetani T 《Biochimica et biophysica acta》2011,1807(10):1253-1261
The cooperative O(2)-binding of hemoglobin (Hb) have been assumed to correlate to change in the quaternary structures of Hb: T(deoxy)- and R(oxy)-quaternary structures, having low and high O(2)-affinities, respectively. Heterotropic allosteric effectors have been shown to interact not only with deoxy- but also oxy-Hbs causing significant reduction in their O(2)-affinities and the modulation of cooperativity. In the presence of two potent effectors, L35 and inositol hexaphosphate (IHP) at pH 6.6, Hb exhibits extremely low O(2)-affinities (K(T)=0.0085mmHg(-1) and K(R)=0.011mmHg(-1)) and thus a very low cooperativity (K(R)/K(T)=1.3 and L(0)=2.4). (1)H-NMR spectra of human adult Hb with these two effectors were examined in order to determine the quaternary state of Hb in solution and to clarify the correlation between the O(2)-affinities and the structural change of Hb caused by the heterotropic effectors. At pH 6.9, (1)H-NMR spectrum of deoxy-Hb in the presence of L35 and IHP showed a marker of the T-quaternary structure (the T-marker) at 14ppm, originated from inter- dimeric α(1)β(2)- (or α(2)β(1)-) hydrogen-bonds, and hyperfine-shifted (hfs) signals around 15-25ppm, caused by high-spin heme-Fe(II)s. Upon addition of O(2), the hfs signals disappeared, reflecting that the heme-Fe(II)s are ligated with O(2), but the T-marker signals still remained, although slightly shifted and broadened, under the partial pressure of O(2) (P(O2)) of 760mmHg. These NMR results accompanying with visible absorption spectroscopy and visible resonance Raman spectroscopy reveal that oxy-Hb in the presence of L35 and IHP below pH 7 takes the ligated T-quaternary structure under the P(O2) of 760mmHg. The L35-concentration dependence of the T-marker in the presence of IHP indicates that there are more than one kind of L35-binding sites in the ligated T-quaternary structure. The stronger binding sites are probably intra-dimeric binding sites between α(1)G- and β(1)G-helices, and the other weaker binding site causes the R→T transition without release of O(2). The fluctuation of the tertiary structure of Hb seems to be caused by both the structural perturbation of α(1)β(1) (or α(2)β(2)) intra-dimeric interface, where the stronger L35-binding sites exist, and by the IHP-binding to the α(1)α(2)- (or β(1)β(2)-) cavity. The tertiary structural fluctuation induced by the allosteric effectors may contribute to the significant reduction of the O(2)-affinity of oxy-Hb, which little depends on the quaternary structures. Therefore, the widely held assumptions of the structure-function correlation of Hb - [the deoxy-state]=[the T-quaternary structure]=[the low O(2)-affinity state] and [the oxy-state]=[the R-quaternary structure]=[the high O(2)-affinity state] and the O(2)-affiny of Hb being regulated by the T/R-quaternary structural transition - are no longer sustainable. This article is part of a Special Issue entitled: Allosteric cooperativity in respiratory proteins. 相似文献
156.
157.
Many pathogens important for medicine, veterinary medicine or public health belong to the genera alphavirus and rubivirus within the family Togaviridae. 29 species of alphaviruses have been reported, and most of them are arboviruses. Chikungnya virus re-emerged in Kenya in 2004 and the epidemics spread to the Indian Ocean islands and many countries in South Asia, South-East Asia and Europe. On the other hand, rubella virus, a sole member of the genus rubivirus, is the causative agent of rubella and congenital rubella syndrome (CRS). Because human is only a natural host of the virus and effective live attenuated vaccines are available, immunization activities are strengthened globally to eliminate rubella and CRS, together with measles. 相似文献
158.
Shah S Otsuki T Fujimura C Yamamoto N Yamashita Y Higaki S Hishinuma M 《Theriogenology》2011,75(4):679-686
The objective was to develop a method for cryopreserving microencapsulated canine sperm. Pooled ejaculates from three beagle dogs were extended in egg yolk tris extender and encapsulated using alginate and poly-L-lysine at room temperature. The microcapsules were cooled at 4 °C, immersed in pre-cooled extender (equivalent in volume to the microcapsules) to reach final concentration of 7% (v/v) glycerol and 0.75% (v/v) Equex STM paste, and equilibrated for 5, 30 and 60 min at 4 °C. Thereafter, microcapsules were loaded into 0.5 mL plastic straws and frozen in liquid nitrogen. In Experiment 1, characteristics of microencapsulated canine sperm were evaluated after glycerol addition at 4 °C. Glycerol exposure for 5, 30 and 60 min did not significantly affect progressive motility, viability, or acrosomal integrity of microencapsulated sperm compared with pre-cooled unencapsulated sperm (control). In Experiment 2, characteristics of frozen-thawed canine microencapsulated sperm were evaluated at 0, 3, 6, and 9 h of culture at 38.5 °C. Pre-freeze glycerol exposure for 5, 30, and 60 min at 4 °C did not influence post-thaw quality in unencapsulated sperm. Post-thaw motility and acrosomal integrity of microencapsulated sperm decreased more than those of unencapsulated sperm (P < 0.05) following glycerol exposure for 5 min. However, motility, viability and acrosomal integrity of microencapsulated sperm after 30 and 60 min glycerol exposure were higher than unencapsulated sperm cultured for 6 or 9 h (P < 0.05). In conclusion, since microencapsulated canine sperm were successfully cryopreserved, this could be a viable alternative to convention sperm cryopreservation in this species. 相似文献
159.
ER-resident Gi2 protein controls sar1 translocation onto the ER during budding of transport vesicles
Nakagawa H Umadome H Miyazaki S Tanaka K Nishimura K Komori M Matsuo S 《Journal of cellular biochemistry》2011,112(9):2250-2256
In our previous study, fluoride ([AlF(4) ](-) ) disturbed ER-to-Golgi transport through the activation of ER-resident heterotrimeric G protein (ER-G protein). Therefore, ER-G protein may be implicated in ER-to-Golgi transport at the early stage prior to coat protein assembly. Sar1 translocation onto the endoplasmic reticulum (ER) membrane is suppressed by non-selective protein kinase inhibitor H89, suggesting the participation of H89-sensitive kinase in this process. To investigate the involvement of ER-G protein in ER-to-Golgi transport, the effect of G(i) protein activator (mastoparan 7) was examined on Sar1 translocation onto the ER in a cell-free system consisting of microsome membrane and cytosol. Sar1 translocation onto the microsome membrane was induced by addition of GTPγS in the cell-free system. Translocation of Sar1 by GTPγS was suppressed significantly by both H89 and mastoparan 7. Mastoparan 7 suppressed the translocation of Sar1 onto the microsome membrane with dosage dependency, but mastoparan 17, the inactive analog of mastoparan 7, had no effect on Sar1 translocation. The suppressive effect of mastoparan 7 was recovered by treatment with pertussis toxin (IAP). Moreover, G(i2) protein was detected on the microsome membrane by western blotting for heterotrimeric G(i) proteins. These results indicate that ER-G(i2) protein modulated Sar1 translocation onto the ER, suggesting that ER-resident G(i2) protein is an important negative regulator of vesicular transport at the early stage of vesicle formation before coat protein assembly on the ER. 相似文献
160.
Yuki Kawakami Shiori Hirano Mai Kinoshita Akemi Otsuki Toshiko Suzuki-Yamamoto Makiko Suzuki Masumi Kimoto Sae Sasabe Mitsuo Fukushima Koji Kishimoto Takashi Izumi Toru Oga Shuh Narumiya Mitsuaki Sugahara Masashi Miyano Shozo Yamamoto Yoshitaka Takahashi 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014