全文获取类型
收费全文 | 110篇 |
免费 | 5篇 |
出版年
2022年 | 3篇 |
2021年 | 2篇 |
2019年 | 1篇 |
2017年 | 1篇 |
2015年 | 1篇 |
2014年 | 3篇 |
2013年 | 3篇 |
2012年 | 12篇 |
2011年 | 6篇 |
2010年 | 3篇 |
2009年 | 2篇 |
2008年 | 8篇 |
2007年 | 11篇 |
2006年 | 9篇 |
2005年 | 6篇 |
2004年 | 9篇 |
2003年 | 5篇 |
2002年 | 4篇 |
2001年 | 2篇 |
2000年 | 2篇 |
1999年 | 1篇 |
1998年 | 1篇 |
1997年 | 1篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1969年 | 1篇 |
1966年 | 1篇 |
1965年 | 2篇 |
1964年 | 1篇 |
1962年 | 2篇 |
1959年 | 1篇 |
1958年 | 3篇 |
1957年 | 1篇 |
1955年 | 3篇 |
1946年 | 1篇 |
1937年 | 1篇 |
排序方式: 共有115条查询结果,搜索用时 578 毫秒
41.
Haines DC Chen B Tomchick DR Bondlela M Hegde A Machius M Peterson JA 《Biochemistry》2008,47(12):3662-3670
P450BM-3 is an extensively studied P450 cytochrome that is naturally fused to a cytochrome P450 reductase domain. Crystal structures of the heme domain of this enzyme have previously generated many insights into features of P450 structure, substrate binding specificity, and conformational changes that occur on substrate binding. Although many P450s are inhibited by imidazole, this compound does not effectively inhibit P450BM-3. Omega-imidazolyl fatty acids have previously been found to be weak inhibitors of the enzyme and show some unusual cooperativity with the substrate lauric acid. We set out to improve the properties of these inhibitors by attaching the omega-imidazolyl fatty acid to the nitrogen of an amino acid group, a tactic that we used previously to increase the potency of substrates. The resulting inhibitors were significantly more potent than their parent compounds lacking the amino acid group. A crystal structure of one of the new inhibitors bound to the heme domain of P450BM-3 reveals that the mode of interaction of the amino acid group with the enzyme is different from that previously observed for acyl amino acid substrates. Further, required movements of residues in the active site to accommodate the imidazole group provide an explanation for the low affinity of imidazole itself. Finally, the previously observed cooperativity with lauric acid is explained by a surprisingly open substrate-access channel lined with hydrophobic residues that could potentially accommodate lauric acid in addition to the inhibitor itself. 相似文献
42.
Whole genome functional analysis identifies novel components required for mitotic spindle integrity in human cells
下载免费PDF全文
![点击此处可从《Genome biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Rines DR Gomez-Ferreria MA Zhou Y DeJesus P Grob S Batalov S Labow M Huesken D Mickanin C Hall J Reinhardt M Natt F Lange J Sharp DJ Chanda SK Caldwell JS 《Genome biology》2008,9(2):R44-12
Background
The mitotic spindle is a complex mechanical apparatus required for accurate segregation of sister chromosomes during mitosis. We designed a genetic screen using automated microscopy to discover factors essential for mitotic progression. Using a RNA interference library of 49,164 double-stranded RNAs targeting 23,835 human genes, we performed a loss of function screen to look for small interfering RNAs that arrest cells in metaphase.Results
Here we report the identification of genes that, when suppressed, result in structural defects in the mitotic spindle leading to bent, twisted, monopolar, or multipolar spindles, and cause cell cycle arrest. We further describe a novel analysis methodology for large-scale RNA interference datasets that relies on supervised clustering of these genes based on Gene Ontology, protein families, tissue expression, and protein-protein interactions.Conclusion
This approach was utilized to classify functionally the identified genes in discrete mitotic processes. We confirmed the identity for a subset of these genes and examined more closely their mechanical role in spindle architecture. 相似文献43.
Meggie Hudspith Jasper M. de Goeij Mischa Streekstra Niklas A. Kornder Jeremy Bougoure Paul Guagliardo Sara Campana Nicole N. van der Wel Gerard Muyzer Laura Rix 《The ISME journal》2022,16(9):2076
The ability of organisms to combine autotrophy and heterotrophy gives rise to one of the most successful nutritional strategies on Earth: mixotrophy. Sponges are integral members of shallow-water ecosystems and many host photosynthetic symbionts, but studies on mixotrophic sponges have focused primarily on species residing in high-light environments. Here, we quantify the contribution of photoautotrophy to the respiratory demand and total carbon diet of the sponge Chondrilla caribensis, which hosts symbiotic cyanobacteria and lives in low-light environments. Although the sponge is net heterotrophic at 20 m water depth, photosynthetically fixed carbon potentially provides up to 52% of the holobiont’s respiratory demand. When considering the total mixotrophic diet, photoautotrophy contributed an estimated 7% to total daily carbon uptake. Visualization of inorganic 13C- and 15N-incorporation using nanoscale secondary ion mass spectrometry (NanoSIMS) at the single-cell level confirmed that a portion of nutrients assimilated by the prokaryotic community was translocated to host cells. Photoautotrophy can thus provide an important supplemental source of carbon for sponges, even in low-light habitats. This trophic plasticity may represent a widespread strategy for net heterotrophic sponges hosting photosymbionts, enabling the host to buffer against periods of nutritional stress.Subject terms: Stable isotope analysis, Microbial ecology, Macroecology 相似文献
44.
Christine Slater Mischa Hardieck Tom Preston Lawrence T. Weaver 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1998,716(1-2)
The use of 13C-labelled compounds to study lipid metabolism is increasing. Typically less than 40% of the orally administered label is recovered in breath CO2. The remainder must be either absorbed and not oxidised or not absorbed and remain in the faeces. Two methods of determining how much tracer passes through the body, and is present in the stool, were compared. Compound specific analysis of tert.-butyldimethylsilyl [13C]hexadecanoic acid by gas chromatography–mass spectrometry (GC–MS) with electron impact ionisation was compared with bulk analysis of whole stool and lipid extract by continuous flow isotope ratio mass spectrometry (CF–IRMS) with a combustion interface. The mean difference between the IRMS and GC–MS methods was −0.02 mmol 13C d−1 with a mean excretion of 14.2 mmol 13C d−1. Combustion IRMS is both simpler and cheaper, when the objective is to determine how much administered dose appears in stool, and information about the form of the label is not required. 相似文献
45.
Brautigam CA Chuang JL Tomchick DR Machius M Chuang DT 《Journal of molecular biology》2005,350(3):543-552
Human dihydrolipoamide dehydrogenase (hE3) is an enzymatic component common to the mitochondrial alpha-ketoacid dehydrogenase and glycine decarboxylase complexes. Mutations to this homodimeric flavoprotein cause the often-fatal human disease known as E3 deficiency. To catalyze the oxidation of dihydrolipoamide, hE3 uses two molecules: non-covalently bound FAD and a transiently bound substrate, NAD+. To address the catalytic mechanism of hE3 and the structural basis for E3 deficiency, the crystal structures of hE3 in the presence of NAD+ or NADH have been determined at resolutions of 2.5A and 2.1A, respectively. Although the overall fold of the enzyme is similar to that of yeast E3, these two structures differ at two loops that protrude from the proteins and at their FAD-binding sites. The structure of oxidized hE3 with NAD+ bound demonstrates that the nicotinamide moiety is not proximal to the FAD. When NADH is present, however, the nicotinamide base stacks directly on the isoalloxazine ring system of the FAD. This is the first time that this mechanistically requisite conformation of NAD+ or NADH has been observed in E3 from any species. Because E3 structures were previously available only from unicellular organisms, speculations regarding the molecular mechanisms of E3 deficiency were based on homology models. The current hE3 structures show directly that the disease-causing mutations occur at three locations in the human enzyme: the dimer interface, the active site, and the FAD and NAD(+)-binding sites. The mechanisms by which these mutations impede the function of hE3 are discussed. 相似文献
46.
Jun Lu Mischa Machius Irina Dulubova Han Dai Thomas C Südhof Diana R Tomchick Josep Rizo 《PLoS biology》2006,4(7)
C 2 domains are well characterized as Ca 2+/phospholipid-binding modules, but little is known about how they mediate protein–protein interactions. In neurons, a Munc13–1 C 2A-domain/RIM zinc-finger domain (ZF) heterodimer couples synaptic vesicle priming to presynaptic plasticity. We now show that the Munc13–1 C 2A domain homodimerizes, and that homodimerization competes with Munc13–1/RIM heterodimerization. X-ray diffraction studies guided by nuclear magnetic resonance (NMR) experiments reveal the crystal structures of the Munc13–1 C 2A-domain homodimer and the Munc13–1 C 2A-domain/RIM ZF heterodimer at 1.44 Å and 1.78 Å resolution, respectively. The C 2A domain adopts a β-sandwich structure with a four-stranded concave side that mediates homodimerization, leading to the formation of an eight-stranded β-barrel. In contrast, heterodimerization involves the bottom tip of the C 2A-domain β-sandwich and a C-terminal α-helical extension, which wrap around the RIM ZF domain. Our results describe the structural basis for a Munc13–1 homodimer–Munc13–1/RIM heterodimer switch that may be crucial for vesicle priming and presynaptic plasticity, uncovering at the same time an unexpected versatility of C 2 domains as protein–protein interaction modules, and illustrating the power of combining NMR spectroscopy and X-ray crystallography to study protein complexes. 相似文献
47.
48.
Induction of Mutants of Staphylococcus aureus 100 with Increased Ability to Produce Enterotoxin A 总被引:7,自引:0,他引:7
下载免费PDF全文
![点击此处可从《Journal of bacteriology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
As a result of serial exposures to a mutagenic agent, N-methyl-N'-nitro-N-nitrosoguanidine, the yield of enterotoxin A produced by the last mutant in the series was increased nearly 20-fold over the amount produced by the parent Staphylococcus aureus 100. 相似文献
49.
Deka RK Brautigam CA Yang XF Blevins JS Machius M Tomchick DR Norgard MV 《The Journal of biological chemistry》2006,281(12):8072-8081
50.
Machius M Wynn RM Chuang JL Li J Kluger R Yu D Tomchick DR Brautigam CA Chuang DT 《Structure (London, England : 1993)》2006,14(2):287-298
The dehydrogenase/decarboxylase (E1b) component of the 4 MD human branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is a thiamin diphosphate (ThDP)-dependent enzyme. We have determined the crystal structures of E1b with ThDP bound intermediates after decarboxylation of alpha-ketoacids. We show that a key tyrosine residue in the E1b active site functions as a conformational switch to reduce the reactivity of the ThDP cofactor through interactions with its thiazolium ring. The intermediates do not assume the often-postulated enamine state, but likely a carbanion state. The carbanion presumably facilitates the second E1b-catalyzed reaction, involving the transfer of an acyl moiety from the intermediate to a lipoic acid prosthetic group in the transacylase (E2b) component of the BCKDC. The tyrosine switch further remodels an E1b loop region to promote E1b binding to E2b. Our results illustrate the versatility of the tyrosine switch in coordinating the catalytic events in E1b by modulating the reactivity of reaction intermediates. 相似文献