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1.
We discuss to what extent the vibrational spectra of bacteriorhodopsin that have been observed and assigned by Smith et al. (1, 2) by means of resonance Raman and by Gerwert and Siebert (EMBO (Eur. Mol. Biol. Organ.) J. In press) by means of infrared absorption experiments are in agreement with a photo-cycle of bacteriorhodopsin that involves the sequence BR, IO(all-trans) → K(13,14-cis) → L(13,14-cis) → M(13-cis) → N(13-cis) → O(all-trans). Our discussion is based on a quantumchemical modified neglect of diatomic overlap [MNDO] calculation of the vibrational spectra of the relevant isomers of the protonated retinal Schiff base. In particular, we investigated in these calculations the effects of different charge environments on the frequencies of the relevant C-C single bond stretching vibrations of these isomers. 相似文献
2.
Structural investigation of bacteriorhodopsin and some of its photoproducts by polarized Fourier transform infrared spectroscopic methods-difference spectroscopy and photoselection 总被引:1,自引:1,他引:0
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The direction of selected IR-transition moments of the retinal chromophore of bacteriorhodopsin (BR) and functional active amino acid residues are determined for light- and dark-adapted BR and for the intermediates K and L of the photocycle. Torsions around single bonds of the chromophore are found to be present in all the investigated BR states. The number of twisted single bonds and the magnitude of these torsions decreases in the order K, L, light-adapted BR, dark-adapted BR. In the last, only the C14—C15 single bond is twisted. The orientation of molecular planes and chemical bonds of such protein side chains, which are perturbed during the transition of light-adapted BR to the respective intermediates, are deduced and the results compared with the current three dimensional model of BR. Trp 86 and Trp 185 are found to form a rigid part of the protein, whereas Asp 96 and Asp 115 perform molecular rearrangements upon formation of the L-intermediate. 相似文献
3.
The ATP binding cassette multidrug transporter LmrA and lipid transporter MsbA have overlapping substrate specificities 总被引:10,自引:0,他引:10
Reuter G Janvilisri T Venter H Shahi S Balakrishnan L van Veen HW 《The Journal of biological chemistry》2003,278(37):35193-35198
LmrA is an ATP binding cassette (ABC) multidrug transporter in Lactococcus lactis that is a structural and functional homologue of the human multidrug resistance P-glycoprotein MDR1 (ABCB1). LmrA is also homologous to MsbA, an essential ABC transporter in Escherichia coli involved in the trafficking of lipids, including Lipid A. We have compared the substrate specificities of LmrA and MsbA in detail. Surprisingly, LmrA was able to functionally substitute for a temperature-sensitive mutant MsbA in E. coli WD2 at non-permissive temperatures, suggesting that LmrA could transport Lipid A. LmrA also exhibited a Lipid A-stimulated, vanadate-sensitive ATPase activity. Reciprocally, the expression of MsbA conferred multidrug resistance on E. coli. Similar to LmrA, MsbA interacted with photoactivatable substrate [3H]azidopine, displayed a daunomycin, vinblastine, and Hoechst 33342-stimulated vanadate-sensitive ATPase activity, and mediated the transport of ethidium from cells and Hoechst 33342 in proteoliposomes containing purified and functionally reconstituted protein. Taken together, these data demonstrate that MsbA and LmrA have overlapping substrate specificities. Our observations imply the presence of structural elements in the recently published crystal structures of MsbA in E. coli and Vibrio cholera (Chang, G., and Roth, C. B. (2001) Science 293, 1793-1800; Chang, G. (2003) J. Mol. Biol. 330, 419-430) that support drug-protein interactions and suggest a possible role for LmrA in lipid trafficking in L. lactis. 相似文献
4.
Velamakanni S Wei SL Janvilisri T van Veen HW 《Journal of bioenergetics and biomembranes》2007,39(5-6):465-471
The ATP-binding cassette (ABC) transporter superfamily is one of the largest protein families with representatives in all
kingdoms of life. Members of this superfamily are involved in a wide variety of transport processes with substrates ranging
from small ions to relatively large polypeptides and polysaccharides. The G subfamily of ABC transporters consists of half-transporters,
which oligomerise to form the functional transporter. While ABCG1, ABCG4 and ABCG5/8 are involved in the ATP-dependent translocation
of steroids and, possibly, other lipids, ABCG2 (also termed the breast cancer resistance protein) has been identified as a
multidrug transporter that confers resistance on tumor cells. Evidence will be summarized suggesting that ABCG2 can also mediate
the binding/transport of non-drug substrates, including free and conjugated steroids. The characterization of the substrate
specificities of ABCG proteins at a molecular level might provide further clues about their potential physiological role(s),
and create new opportunities for the modulation of their activities in relation to human disease. 相似文献
5.
Janvilisri T Likitponrak W Chunchob S Grams R Vichasri-Grams S 《Molecular and cellular biochemistry》2007,305(1-2):95-102
Fatty acid binding proteins (FABPs) are capable of binding hydrophobic ligands with high affinity; thereby facilitating the
cellular uptake and intracellular trafficking of fatty acids. In this study, functional characteristics of a cytoplasmic FABP
from the giant liver fluke Fasciola gigantica (FgFABP) were determined. Binding of a fluorescent fatty acid analogue 11-[[5-dimethy aminonaphtalene-1-sulphonyl] amino]
undecanoic acid (DAUDA) to FgFABP resulted in changes in the emission spectrum. The optimal excitation wavelength and maximum
emission of fluorescence for binding activities with DAUDA were 350 nm and 550 nm, respectively. The binding activity for
DAUDA was determined from titration experiments and revealed a Kd value of 2.95 ± 0.54 μM. Furthermore, we found that cross-linking profile of FgFABP with dithiobis-(succinimidylpropionate)
(DSP) in the presence of DAUDA resulted in increased formation of higher-ordered oligomers compared to that in the absence
of DAUDA. We also replaced five highly conserved positively charged residues (K9, K58, K91, R107 and K131) with alanine and
studied their oligomerization and binding properties of the modified FgFABPs. The obtained data demonstrate that these residues
do not appear to be involved in oligomerization. However, the K58A and R107A substitutions exhibited a reduction in binding
affinities. K91A and R107A revealed an increase in maximal specific binding. 相似文献
6.
Systematic identification of antiprion drugs by high-throughput screening based on scanning for intensely fluorescent targets 总被引:3,自引:0,他引:3
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Bertsch U Winklhofer KF Hirschberger T Bieschke J Weber P Hartl FU Tavan P Tatzelt J Kretzschmar HA Giese A 《Journal of virology》2005,79(12):7785-7791
Conformational changes and aggregation of specific proteins are hallmarks of a number of diseases, like Alzheimer's disease, Parkinson's disease, and prion diseases. In the case of prion diseases, the prion protein (PrP), a neuronal glycoprotein, undergoes a conformational change from the normal, mainly alpha-helical conformation to a disease-associated, mainly beta-sheeted scrapie isoform (PrP(Sc)), which forms amyloid aggregates. This conversion, which is crucial for disease progression, depends on direct PrP(C)/PrP(Sc) interaction. We developed a high-throughput assay based on scanning for intensely fluorescent targets (SIFT) for the identification of drugs which interfere with this interaction at the molecular level. Screening of a library of 10,000 drug-like compounds yielded 256 primary hits, 80 of which were confirmed by dose response curves with half-maximal inhibitory effects ranging from 0.3 to 60 microM. Among these, six compounds displayed an inhibitory effect on PrP(Sc) propagation in scrapie-infected N2a cells. Four of these candidate drugs share an N'-benzylidene-benzohydrazide core structure. Thus, the combination of high-throughput in vitro assay with the established cell culture system provides a rapid and efficient method to identify new antiprion drugs, which corroborates that interaction of PrP(C) and PrP(Sc) is a crucial molecular step in the propagation of prions. Moreover, SIFT-based screening may facilitate the search for drugs against other diseases linked to protein aggregation. 相似文献
7.
The molecular structures of amyloid fibers characterizing neurodegenerative diseases such as Huntington's or transmissible spongiform encephalopathies are unknown. Recently, x-ray diffraction patterns of poly-Gln fibers and electron microscopy images of two-dimensional crystals formed from building blocks of prion rods have suggested that the corresponding amyloid fibers are generated by the aggregation of parallel beta-helices. To explore this intriguing concept, we study the stability of small beta-helices in aqueous solution by molecular dynamics simulations. In particular, for the Huntington aggregation nucleus, which is thought to be formed of poly-Gln polymers, we show that three-coiled beta-helices are unstable at the suggested circular geometries and stable at a triangular shape with 18 residues per coil. Moreover, we demonstrate that individually unstable two-coiled triangular poly-Gln beta-helices become stabilized upon dimerization, suggesting that seeded aggregation of Huntington amyloids requires dimers of at least 36 Gln repeats (or monomers of approximately 54 Gln) for the formation of sufficiently stable aggregation nuclei. An analysis of our results and of sequences occurring in native beta-helices leads us to the proposal of a revised model for the PrP(Sc) aggregation nucleus. 相似文献
8.
Varyukhina S Freitas M Bardin S Robillard E Tavan E Sapin C Grill JP Trugnan G 《Microbes and infection / Institut Pasteur》2012,14(3):273-278
Rotaviruses attach to intestinal cells in a process that requires glycan recognition. Some bacteria from the gut microflora have been shown to modify cell-surface glycans. In this study, human intestinal cultured cells were incubated with bacteria-derived soluble factors and infected with rotavirus. Results show that only bacterial soluble factors that increase cell-surface galactose namely, those of Bacteroides thetaiotaomicron and Lactobacillus casei were able to efficiently block rotavirus infections. Increasing cell-surface galactose using galactosyltransferase resulted in a similar blockage of rotavirus infections. These results indicate that manipulation of cell-surface intestinal glycans by bacterial soluble factors can prevent rotavirus infection in a species-specific manner, and should now be considered a potential therapeutic approach against rotavirus infection. 相似文献
9.
The Effect of Protonation and Electrical Interactions on the Stereochemistry of Retinal Schiff Bases 总被引:2,自引:1,他引:1
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Based on quantumchemical MNDOC calculations it is shown that the ground-state properties of a retinal Schiff base depend sensitively on its protonation state and charge environment. This is exemplified for the equilibrium geometry, for the distribution of partial charges and, in particular, for the thermal isomerization barriers around the π-bonds. It is demonstrated that a protein, by protonating the retinal Schiff base and by providing one or two negative ions in its environment, can reduce double-bond isomerization barriers from 50 kcal/mol for the unprotonated compound to ~ 5 kcal/mol and can increase single bond barriers from 5 kcal/mol to ~ 20 kcal/mol. Thereby, the specific location of the ions relative to the polyene chain of the protonated retinal Schiff base determines the barrier heights. The results explain the ground-state isomerization reactions of retinal observed in bacteriorhodopsin and in squid retinochrome. 相似文献
10.
We present random walk models for the diffusive motion of lipid probe molecules in a lipid bilayer and calculate the diffusion constants for probes spanning the entire bilayer and for probes extending through one lipid layer only. The stiffness of such molecules can explain the observed value of 2/3 for the ratio of these diffusion constants. 相似文献