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81.
Structural disorder in the complex of human pregnane X receptor and the macrolide antibiotic rifampicin 总被引:6,自引:0,他引:6
Chrencik JE Orans J Moore LB Xue Y Peng L Collins JL Wisely GB Lambert MH Kliewer SA Redinbo MR 《Molecular endocrinology (Baltimore, Md.)》2005,19(5):1125-1134
The human nuclear xenobiotic receptor, pregnane X receptor (PXR), detects a variety of structurally distinct endogenous and xenobiotic compounds and controls expression of genes central to drug and cholesterol metabolism. The macrolide antibiotic rifampicin, a front-line treatment for tuberculosis, is an established PXR agonist and, at 823 Da, is one of the largest known ligands for the receptor. We present the 2.8 A crystal structure of the ligand-binding domain of human PXR in complex with rifampicin. We also use structural and mutagenesis data to examine the origins of the directed promiscuity exhibited by the PXRs across species. Three structurally flexible loops adjacent to the ligand-binding pocket of PXR are disordered in this crystal structure, including the 200-210 region that is part of a sequence insert novel to the promiscuous PXRs relative to other members of the nuclear receptor superfamily. The 4-methyl-1-piperazinyl ring of rifampicin, which would lie adjacent to the disordered protein regions, is also disordered and not observed in the structure. Taken together, our results indicate that one wall of the PXR ligand-binding cavity can remain flexible even when the receptor is in complex with an activating ligand. These observations highlight the key role that structural flexibility plays in PXR's promiscuous response to xenobiotics. 相似文献
82.
Wisely SM Buskirk SW Fleming MA McDonald DB Ostrander EA 《The Journal of heredity》2002,93(4):231-237
The black-footed ferret (Mustela nigripes) is an endangered North American carnivore that underwent a well-documented population bottleneck in the mid-1980s. To better understand the effects of a bottleneck on a free-ranging carnivore population, we used 24 microsatellite loci to compare genetic diversity before versus during the bottleneck, and compare the last wild population to two historical populations. We also compared genetic diversity in black-footed ferrets to that of two sibling species, the steppe polecat (Mustela eversmanni) and the European polecat (Mustela putorius). Black-footed ferrets during the bottleneck had less genetic diversity than steppe polecats. The three black-footed ferret populations were well differentiated (F(ST) = 0.57 +/- 0.15; mean +/- SE). We attributed the decrease in genetic diversity in black-footed ferrets to localized extinction of these genetically distinct subpopulations and to the bottleneck in the surviving subpopulation. Although genetic diversity decreased, female fecundity and juvenile survival were not affected by the population bottleneck. 相似文献
83.
ANETT HARSÁNYI MARGARETA RYBERG MATS X. ANDERSSON KÁROLY BÓKA LAJOS LÁSZLÓ GERGELY BOTOND BÉLA BÖDDI RICHARD GÁBORJÁNYI 《Molecular Plant Pathology》2006,7(6):533-541
To understand the phenomenon by which infection of seed-transmitted Barley stripe mosaic virus (BSMV) alters membrane structures and inhibits protochlorophyllide biosynthesis of dark-grown barley ( Hordeum vulgare L.) plants, we analysed the presence of NADPH:protochlorophyllide oxidoreductase (POR, EC 1.3.1.33) and the galactolipid content and fatty acid composition. The amount of POR in etioplasts of infected leaves, compared with non-infected leaves, was reduced, as measured by immunoelectron microscopy and Western blot. These results are in agreement with the previously described reduction of the ratio of the photoactive 650 nm to non-photoactive 630 nm absorbing protochlorophyllide forms ( Harsányi et al. , 2002 . Physiol. Plant 114 , 149–155). The galactolipid content was lower in infected leaves. Monogalactosyl-diacylglycerol (MGDG) content was reduced to 40% and digalactosyl-diacylglycerol to 55% of control plants on a fresh weight basis. In infected plants, the proportion of linolenic acid decreased in both galactolipids. The lower amount of highly unsaturated fatty acids and the reduced abundance of MGDG correlated well with the previously detected reduction in the membrane ratio of prolamellar body (PLB) to prothylakoid ( Harsányi et al. , 2002 . Physiol. Plant 114 , 149–155). The reduced amount of POR and the above described alterations in the lipid composition resulted in a disturbed structure of PLBs. As a consequence, pigment synthesis and the greening process were inhibited in infected cells, in turn explaining the appearance of chlorotic stripes of BSMV-infected barley leaves. Our results show that BSMV infection can be detected at a very early stage of leaf development. 相似文献
84.
Molecular recognition of fatty acids by peroxisome proliferator-activated receptors 总被引:13,自引:0,他引:13
Xu HE Lambert MH Montana VG Parks DJ Blanchard SG Brown PJ Sternbach DD Lehmann JM Wisely GB Willson TM Kliewer SA Milburn MV 《Molecular cell》1999,3(3):397-403
The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors for fatty acids (FAs) that regulate glucose and lipid homeostasis. We report the crystal structure of the PPAR delta ligand-binding domain (LBD) bound to either the FA eicosapentaenoic acid (EPA) or the synthetic fibrate GW2433. The carboxylic acids of EPA and GW2433 interact directly with the activation function 2 (AF-2) helix. The hydrophobic tail of EPA adopts two distinct conformations within the large hydrophobic cavity. GW2433 occupies essentially the same space as EPA bound in both conformations. These structures provide molecular insight into the propensity for PPARs to interact with a variety of synthetic and natural compounds, including FAs that vary in both chain length and degree of saturation. 相似文献
85.
The biogeochemistry of basic cations in two forest catchments with contrasting lithology in the Czech Republic 总被引:2,自引:0,他引:2
PAVEL KRÁM JAKUB HRUŠKA BRIAN S. WENNER CHARLES T. DISCOLL CHRIS E. JOHNSON 《Biogeochemistry》1997,37(2):173-202
The biogeochemistry of Ca, Mg, K, and Nawere investigated in two forested catchments in theCzech Republic, one underlain by leucogranite, theother by serpentinite. High weathering rates at theserpentinite site at Pluhv Bor resultedin Mg2+ as the dominant cation on the soilexchange complex and in drainage water. Other basiccations (Ca2+, K+, Na+) showedrelatively low concentrations and outflow instreamwater. The catchment exhibited high basesaturation in mineral soils (>70%), and nearneutral soil and stream pH, despite elevated inputsof acidic deposition. Slow growth of Norway spruceat Pluhv Bor may be caused by K deficiency, Mgoversupply and/or Ni toxicity. In contrast, thegranitic site at Lysina showed low concentrations ofbasic cations on the soil exchange complex and instreamwater. Soil and drainage water at Lysina werehighly impacted by acidic deposition. Soil pH wasextremely acidic (<4.5) throughout the soilprofile, and the base saturation of the mineral soilwas very low (<5%). Supplies of basic cationsfrom atmospheric deposition and soil processes wereless than inputs of SO2-
4 on anequivalence basis, resulting in low pH and highconcentrations of total Al in drainage water. Needle yellowing in Norway spruce was possibly theresult of Mg deficiency at Lysina. Because of theirextremely different lithologies, these catchmentsserve as valuable end-members of ecosystemsensitivity to elevated levels of acidicdeposition. 相似文献
86.
Angstrom J; Teneberg S; Milh MA; Larsson T; Leonardsson I; Olsson BM; Halvarsson MO; Danielsson D; N aslund I; Ljungh A; Wadstrom T; Karlsson KA 《Glycobiology》1998,8(4):297-309
The possible role of glycosphingolipids as adhesion receptors for the human
gastric pathogen Helicobacter pylori was examined by use of radiolabeled
bacteria, or protein extracts from the bacterial cell surface, in the
thin-layer chromatogram binding assay. Of several binding specificities
found, the binding to lactosylceramide is described in detail here, the
others being reported elsewhere. By autoradiography a preferential binding
to lactosylceramide having sphingosine/phytosphingosine and 2-D hydroxy
fatty acids was detected, whereas lactosylceramide having sphingosine and
nonhydroxy fatty acids was consistently nonbinding. A selective binding of
H. pylori to lactosylceramide with phytosphingosine and 2-D hydroxy fatty
acid was obtained when the different lactosylceramide species were
incorporated into liposomes, but only in the presence of cholesterol,
suggesting that this selectivity may be present also in vivo . Importantly,
lactosylceramide with sphingosine and hydroxy fatty acids does not bind in
this assay. Furthermore, a lactosylceramide-based binding pattern obtained
for different trisaccharide glycosphingolipids is consistent with the
assumption that this selectivity is due to binding of a conformation of
lactosylceramide in which the oxygen of the 2-D fatty acid hydroxyl group
forms a hydrogen bond with the Glc hydroxy methyl group, yielding an
epitope presentation different from other possible conformers. An
alternative conformation that may come into consideration corresponds to
the crystal structure found for cerebroside, in which the fatty acid
hydroxyl group is free to interact directly with the adhesin. By isolating
glycosphingolipids from epithelial cells of human stomach from seven
individuals, a binding of H.pylori to the diglycosylceramide region of the
non-acid fraction could be demonstrated in one of these cases. Mass
spectrometry showed that the binding-active sample contained
diglycosylceramides with phytosphingosine and 2-D hydroxy fatty acids with
16-24 carbon atoms in agreement with the results related above.
相似文献
87.
Moreno E; Lanne B; Vazquez AM; Kawashima I; Tai T; Fernandez LE; Karlsson KA; Angstrom J; Perez R 《Glycobiology》1998,8(7):695-705
P3 is a mouse monoclonal antibody (mAb) that binds to several NeuGc-
containing gangliosides. It also reacts with antigens expressed in human
breast tumors (Vazquez et al. (1995) Hybridoma , 14, 551-556). In this
work, the binding specificity of P3 has been characterized in more detail
using a panel of glycolipids that included several disialylated
gangliosides and several chemical derivatives of NeuGc-GM3. The carboxyl
group and the nitrogen function of sialic acid were found to play important
roles in the antibody binding, whereas the glycerol tail appears to be
nonrelevant. Molecular modeling was used to analyze the binding data,
including the finding that P3 selectively recognizes the internal NeuGc in
GD3. For this purpose, conformational studies of GD3 were performed using
molecular dynamics. It was concluded that sialic acid binds the P3 antibody
through its upper face (the one on which the carboxyl group is exposed) and
the C4-C5 side of the sugar ring, whereas none or very little contact
between the galactose residue and the protein is evident. Conformational
analysis of GD3 revealed that, despite the large flexibility of the
NeuGcalpha8NeuGc linkage, the P3 binding epitope on the external sialic
acid is not well exposed for any of the possible conformations this linkage
can adopt, whereas the internal sialic acid presents the epitope in a
proper way for several of these conformations. As a final result, a
coherent picture of the epitope that fits the wide binding data was
obtained.
相似文献
88.
Walter RB; Rolig RL; Kozak KA; McEntire B; Morizot DC; Nairn RS 《Molecular biology and evolution》1993,10(6):1227-1238
Fishes represent the stem vertebrate condition and have maintained several
gene arrangements common to mammalian genomes throughout the 450 Myr of
divergence from a common ancestor. One such syntenic arrangement includes
the GPI-PEPD enzyme association on Xiphophorus linkage group IV and human
chromosome 19. Previously we assigned the Xiphophorus homologue of the
human ERCC2 gene to linkage group U5 in tight association with the CKM
locus. CKM is also tightly linked to the ERCC2 locus on human chromosome
19, leading to speculation that human chromosome 19 may have arisen by
fusion of two ancestral linkage groups which have been maintained in
fishes. To investigate this hypothesis further, we isolated and sequenced
Xiphophorus fish genomic regions exhibiting considerable sequence
similarity to the human DNA ligase 1 amino acid sequence. Comparison of the
fish DNA ligase sequence with those of other species suggests several modes
of amino acid conservation in this gene. A 2.2-kb restriction fragment
containing part of an X. maculatus DNA ligase 1 exon was used in backcross
hybrid mapping with 12 enzyme or RFLP loci. Significant linkage was
observed between the nucleoside phosphorylase (NP2) and the DNA ligase
(LIG1) loci on Xiphophorus linkage group VI. This assignment suggests that
the association of four DNA repair-related genes on human chromosome 19 may
be the result of chance chromosomal rearrangements.
相似文献
89.
ZDENEK IKA 《The Journal of eukaryotic microbiology》1972,19(2):275-280
SYNOPSIS. In an electron microscope study of the neogregarine Farinocystis tribolii Weiser 1953 in the fat body of the larvae of the flour beetle Tribolium castaneum , empty oocysts and adjacent sporozoites of the gregarine were found. The empty oocysts contained host cell cytoplasm, a residuum only slightly larger than that in mature oocysts, and some remnants of the oocyst membrane pressed tightly against the inner surface of the wall. Apparently normal sporozoites were found near the empty oocysts and no damaged ones were seen. It is assumed that the sporozoites go on developing in the host, i.e., that autoinfection takes place. 相似文献
90.
Restriction mapping is used to estimate nucleotide sequence polymorphism
when the regions to be studied are too long or too numerous to be
sequenced. Restriction mapping is less costly than DNA sequencing, but it
does not allow direct measurement of underlying nucleotide polymorphism. It
is therefore useful to be able to estimate underlying nucleotide
polymorphism from observations of polymorphism in restriction maps, as this
offers some of the resolution afforded by DNA sequencing at a reduced cost.
Previous estimators of underlying nucleotide polymorphism have assumed that
each restriction-enzyme- binding site contains, at most, a single
polymorphic nucleotide position (the low-polymorphism-frequency
assumption), and this assumption has placed an upper limit on the level of
polymorphism that can be resolved by these estimators. The present study
documents an estimator which allows relaxation of this assumption. The new
estimator more accurately estimates underlying nucleotide polymorphism when
the polymorphism level is high enough to falsify the low-polymorphism-
frequency assumption. The new estimator therefore yields good results for
data sets that are too divergent for analysis by present methods.
相似文献