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201.
Ishino T Urbina C Bhattacharya M Panarello D Chaiken I 《The Journal of biological chemistry》2005,280(24):22951-22961
The cyclic peptide AF17121 is a library-derived antagonist for human interleukin-5 (IL5) receptor alpha (IL5Ralpha) and inhibits IL5 activity. Our previous results have demonstrated that the sixth arginine residue of the peptide is crucial for the inhibitory effect and that several acidic residues in the N- and C-terminal regions also make a contribution, although to a lesser extent (Ruchala, P., Varadi, G., Ishino, T., Scibek, J., Bhattacharya, M., Urbina, C., Van Ryk, D., Uings, I., and Chaiken, I. (2004) Biopolymers 73, 556-568). However, the recognition mechanism of the receptor has remained unresolved. In this study, AF17121 was fused to thioredoxin by recombinant DNA techniques and examined for IL5Ralpha interaction using a surface plasmon resonance biosensor method. Kinetic analysis revealed that the dissociation rate of the peptide.receptor complex is comparable with that of the cytokine.receptor complex. The fusion peptide competed with IL5 for both biological function and interaction with IL5Ralpha, indicating that the binding sites on the receptor are shared by AF17121 and IL5. To define the epitope residues for AF17121, we defined its binding footprint on IL5Ralpha by alanine substitution of Asp(55), Asp(56), Glu(58), Lys(186), Arg(188), and Arg(297) of the receptor. Marked effects on the interaction were observed in all three fibronectin type III domains of IL5Ralpha, in particular Asp(55), Arg(188), and Arg(297) in the D1, D2, and D3 domains, respectively. This footprint represents a significant subset of that for IL5 binding. The fact that AF17121 mimics the receptor binding capability of IL5 but antagonizes biological function evokes several models for how IL5 induces activation of the multisubunit receptor system. 相似文献
202.
Profilin is an actin monomer-binding protein implicated in the polymerization of actin filaments. In the budding yeast Saccharomyces cerevisiae, the pfy1-111 rho2delta double mutant has severe growth and actin cytoskeletal defects. The GEA1 and GEA2 genes, which code for paralog guanosine exchange factors for Arf proteins, were identified as multicopy suppressors of the mutant phenotype. These two genes restored the polarized distribution of actin cortical patches and produced visible actin cables in both the pfy1-111 rho2delta and pfy1delta cells. Thus, overexpression of GEA1 or GEA2 bypassed the requirement for profilin in actin cable formation. In addition, gea1 gea2 double mutants showed defects in budding and in actin cytoskeleton organization, while overexpression of GEA1 or GEA2 led to the formation of supernumerary actin cable-like structures in a Bni1p/Bnr1p-dependent manner. The ADP-ribosylation factor Arf3p may be a target of Gea1p/Gea2p, since overexpression of ARF3 partially suppressed the profilin-deficient phenotype and a deletion of ARF3 exacerbated the phenotype of a pfy1-111 mutant. Gea1p, Gea2p, Arf1p, and Arf2p but not Arf3p are known to function in vesicular transport between the endoplasmic reticulum and the Golgi. In this work, we demonstrate a role for Gea1p, Gea2p, and Arf3p in the organization of the actin cytoskeleton. 相似文献
203.
Ksander GM Shetty SS DelGrande D Balwierczak JL Bruseo CW Savage P deJesus R Yuan A Webb RL Jeng AY 《Canadian journal of physiology and pharmacology》2002,80(5):464-469
Endothelin-1 (ET-1) is a potent mitogen and modulator of vascular tone. It is synthesized and released from endothelial cells and acts upon two receptor subtypes designated as ETA and ETB. In this study, a series of potent dipeptide sulfonamide dual-endothelin ETA/ETB receptor antagonists were prepared to investigate their potential benefit in vascular diseases. CGS 31398 inhibited [125I]ET-1 binding to human ETA and ETB receptors expressed in Chinese hamster ovary (CHO) cells (ETA/CHO, ETB/CHO) with respective IC50 values of 0.26 and 0.12 nM. However, in anesthetized rats, this compound markedly potentiated ET-1-induced renal vascular resistance, a response normally observed with selective ETB receptor antagonists. To determine whether species differences account for these results, a direct comparison was made between binding to rat and rabbit aortic membranes versus functional antagonism in isolated rat aortic rings. It was found that CGS 31398 had potent affinity for the ETA receptor in rat and rabbit aorta with IC50 values of 0.87 and 0.79 nM, respectively. Inhibition of ET-1-induced contractions of rat aorta by the compound was considerably weaker than expected (pKB = 6.4), while that of sarafotoxin S6c induced contraction of dog saphenous vein (100% inhibition at 100 nM) was consistent with corresponding binding data. These results suggest that although CGS 31398 is a potent dual inhibitor of ETA/ETB receptor binding, it surprisingly displays potent ETB and weak ETA receptor antagonism in functional assays. 相似文献
204.
Williams J Taylor P Bogacki P Pallotta M Bariana S Wallwork H 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2002,104(5):874-879
The root lesion nematode, Pratylenchus neglectus, is an economically damaging pathogen of wheat and other crops. The development of P. neglectus-resistant wheat cultivars would be greatly accelerated through the use of molecular markers, as resistance phenotyping is extremely time-consuming. A greenhouse bioassay was developed to identify resistance phenotypes of doubled-haploid populations. Bulked-segregant analysis was used to identify AFLP markers linked to P. neglectus resistance in the wheat cultivar Excalibur. One resistance-linked AFLP marker was mapped close to chromosome 7A RFLP markers in a densely-mapped Cranbrook/Halberd population. One of the chromosome 7A RFLP probes, cdo347, was genotyped in the Tammin/Excalibur population segregating for response to root lesion nematode and showed 8% recombination with the P. neglectus resistance gene Rlnn1. The marker Xcdo347-7A was validated on Excalibur-and Krichauff-derived DH populations segregating for Rlnn1 and showed 14% and 10% recombination, respectively, with Rlnn1 in these populations. 相似文献
205.
Mendola D 《Biomolecular engineering》2003,20(4-6):441-458
Large-scale, renewable supplies of chemical constituents derived from marine invertebrates have limited development of potential new natural product drugs. This paper describes the development of two in-sea aquaculture systems designed and engineered for production of large quantities of biomass for two species of marine invertebrates desired for their natural product chemical constituents. The two invertebrates and their products were: (1) the cosmopolitan, arborescent bryozoan Bugula neritina (Phylum Bryozoa) for its anticancer chemical constituent bryostatin 1; and (2) Ecteinascidia turbinate (Phylum Tunicata) the source of anticancer ecteinascidin 743. For the third invertebrate Phylum Porifera, and its representative sponge Acanthella cavernosa (desired for its anti-parasitic and anti-infective kalihinols) in-sea systems were not developed in favor of controlled environment tank aquaculture systems. For the bryozoan and tunicate, projected economics for commercial-scale in-sea production proved cost effective. This was in contrast to the controlled environment sponge culture tank system, which did not prove to be economical due to inherent slow growth and low natural product yields of the sponge in culture. A non-destructive method for "milking" natural product chemicals from sponges was tested and is described. 相似文献
206.
Desai RC Gratale DF Han W Koyama H Metzger E Lombardo VK MacNaul KL Doebber TW Berger JP Leung K Franklin R Moller DE Heck JV Sahoo SP 《Bioorganic & medicinal chemistry letters》2003,13(20):3541-3544
A series of novel aryloxazolidine-2,4-diones was synthesized. A structure-activity relationship study of these compounds led to the identification of potent, orally active PPAR dual alpha/gamma agonists. Based on the results of efficacy studies in the db/db mice model of type 2 diabetes and the desired pharmacokinetic parameters, compound 12 was selected for further profiling. 相似文献
207.
Based on positive results for 11 of 17 species included in an anatomical survey of tree roots, we concluded that the origin of adventitious branch roots (ABR) on established, undisturbed woody parental root axes is a widespread occurrence. ABR were morphologically indistinguishable from branch roots formed in primary tissues of a parental axis, and they occurred without increase in branch root density. We concluded that ABR are an unrecognized component of undamaged root systems. Using continuous serial sectioning to perform a census of branch roots within parental root axes, we obtained definitive evidence that ABR participate in root turnover. Comparisons of older and younger axes, and the chronology of root formation in older axes fulfilled the expectation that with greater age of parental axis, ABR become increasingly predominant among intact branch roots. We confirmed this trend for one of the species scoring negative in the survey, which means that our survey results were probably influenced by age variation. Thus, any of the six negative results obtained in the survey may have been dependent on the young age and slenderness of the axes that were available for examination in those six species. 相似文献
208.
Increase of membrane permeability of mitochondria isolated from water stress adapted potato cells 总被引:4,自引:0,他引:4
In order to gain some insight into mitochondria permeability under water stress, intact coupled mitochondria were isolated from water stress adapted potato cells and investigations were made of certain transport processes including the succinate/malate and ADP/ATP exchanges, the plant mitochondrial ATP-sensitive potassium channel (PmitoKATP) and the plant uncoupling mitochondrial protein (PUMP). The V
maxL values measured for succinate/malate and ADP/ATP carriers, as photometrically investigated, as well as the same values for the PmitoATP and the PUMP were found to increase; this suggested that mitochondria adaptation to water stress can cause an increase in the membrane permeability. 相似文献
209.
Two morphogenetic patterns have contributed to phylogenetic diversification within the Gesneriaceae: accrescence of one of the paired cotyledons (anisocotyly), which serves to differentiate the subfamily Cyrtandroideae; sustained growth of the accrescent cotyledon accompanied by prolonged suppression and displacement of the embryonic apical meristem, which gives rise to an acaulescent, dorsiventral vegetative plant body (phyllomorph) and further serves to differentiate species of Cyrtandroideae found in two tribes and several genera including Streptocarpus. It was possible to prevent cotyledonary accrescence and induce caulescence at will, either by supplying exogenous GA3 or inhibiting auxin transport in species of Streptocarpus that normally manifest an extreme, phyllomorphic morphology. It was also possible to induce sustained, phyllomorphic development of cotyledons that are normally non-accrescent with exogenous cytokinin. Therefore morphogenetic capacities previously thought to be “lost” or “lacking” in subgenus Streptocarpus and, with respect to isocotyly, the tribe Cyrtandroideae, are, in fact, present but suppressed. An hypothesis regarding the role of hormones with respect to morphogenesis and phylogeny of Streptocarpus is suggested. 相似文献
210.
Chaika NV Yu F Purohit V Mehla K Lazenby AJ DiMaio D Anderson JM Yeh JJ Johnson KR Hollingsworth MA Singh PK 《PloS one》2012,7(3):e32996