全文获取类型
收费全文 | 725篇 |
免费 | 122篇 |
出版年
2021年 | 6篇 |
2020年 | 6篇 |
2019年 | 6篇 |
2017年 | 5篇 |
2016年 | 15篇 |
2015年 | 15篇 |
2014年 | 22篇 |
2013年 | 22篇 |
2012年 | 38篇 |
2011年 | 37篇 |
2010年 | 26篇 |
2009年 | 19篇 |
2008年 | 29篇 |
2007年 | 42篇 |
2006年 | 36篇 |
2005年 | 43篇 |
2004年 | 22篇 |
2003年 | 44篇 |
2002年 | 39篇 |
2001年 | 18篇 |
2000年 | 20篇 |
1999年 | 24篇 |
1998年 | 11篇 |
1997年 | 9篇 |
1996年 | 15篇 |
1995年 | 15篇 |
1994年 | 10篇 |
1993年 | 9篇 |
1992年 | 12篇 |
1991年 | 9篇 |
1990年 | 21篇 |
1989年 | 12篇 |
1988年 | 12篇 |
1987年 | 15篇 |
1986年 | 8篇 |
1985年 | 6篇 |
1984年 | 8篇 |
1983年 | 10篇 |
1982年 | 13篇 |
1980年 | 7篇 |
1979年 | 4篇 |
1977年 | 6篇 |
1976年 | 7篇 |
1974年 | 15篇 |
1973年 | 4篇 |
1969年 | 4篇 |
1968年 | 8篇 |
1967年 | 7篇 |
1963年 | 5篇 |
1928年 | 4篇 |
排序方式: 共有847条查询结果,搜索用时 31 毫秒
61.
Tail-anchored proteins form a distinct class of membrane proteins that have a single membrane anchor sequence at their C-terminus, the tail-anchor. Their N-terminal portion is exposed to the cytosol. We have studied the roles of tail-anchor domains of proteins residing in the mitochondrial outer membrane. Four distinct functions of the tail-anchor domain were identified. First, the domain mediates the targeting to mitochondria in a process that probably requires a net positive charge at the C-terminally flanking segment. Second, tail-anchor domains facilitate the insertion into the mitochondrial outer membrane. Third, the tail-anchor is responsible for the assembly of the respective protein into functional multi-subunit complexes; and fourth, tail-anchor domains can stabilize such complexes. 相似文献
62.
Previous work from our laboratory (Athenstaedt, K., Zweytick, D., Jandrositz, A., Kohlwein, S. D., and Daum, G. (1999) J. Bacteriol. 181, 6441-6448) showed that the gene product of YMR313c (named Tgl3p) is a component of yeast lipid particles, and deletion of this gene led to an increase in the cellular level of triacylglycerols (TAG). These observations suggested that TGL3 may encode a TAG lipase of Saccharomyces cerevisiae. Here we demonstrate by cell fractionation and by microscopic inspection of a strain bearing a Tgl3p-GFP hybrid that this polypeptide is highly enriched in the lipid particle fraction but virtually absent from other organelles. The entire TAG lipase activity of lipid particles is attributed to Tgl3p, because the activity in this organelle is completely absent in a Deltatgl3 deletion mutant, whereas it is significantly enhanced in a strain overexpressing Tgl3p. A His6-tagged Tgl3p hybrid purified close to homogeneity from a yeast strain overexpressing this fusion protein exhibited high TAG lipase activity. Most importantly, experiments in vivo using the fatty acid synthesis inhibitor cerulenin demonstrated that deletion of TGL3 resulted in a decreased mobilization of TAG from lipid particles. The amino acid sequence deduced from the open reading frame YMR313c contains the consensus sequence motif GXSXG typical for lipolytic enzymes. Otherwise, Tgl3p has no significant sequence homology to other lipases identified so far. In summary, our data identified Tgl3p as a novel yeast TAG lipase at the molecular level and by function in vivo and in vitro. 相似文献
63.
64.
Environmental enrichment for rodents is beneficial, but compatibility between the enrichment device and the rodent strain must also be considered. The authors present a case in which the use of a specific form of environmental enrichment--cotton bedding material--proved detrimental to the health of athymic nude mice, increasing the likelihood of conjunctivitis. 相似文献
65.
The major chaperone genes of Helicobacter pylori are negatively regulated by HspR, a homologue of the repressor of the dnaK operon of Streptomyces coelicolor. Using an in vitro selection and amplification approach we identified two new chromosomal binding sites of the HspR protein. Both binding sites were characterized by footprinting analysis with purified HspR protein. Intriguingly, these HspR binding sites are located at the 3prime prime or minute ends of two genes coding for predicted proteins with functions unrelated to those of chaperones. This suggests that H. pylori HspR may regulate the expression of genes encoding proteins with diverse functions. Nucleotide sequence alignment of HspR-binding sites highlights conserved nucleotides extending outside the previously proposed consensus binding sequence with structural features predicting geometry of HspR binding as an oligomer. 相似文献
66.
67.
Structure determination of T cell protein-tyrosine phosphatase 总被引:2,自引:0,他引:2
Iversen LF Moller KB Pedersen AK Peters GH Petersen AS Andersen HS Branner S Mortensen SB Moller NP 《The Journal of biological chemistry》2002,277(22):19982-19990
Protein-tyrosine phosphatase 1B (PTP1B) has recently received much attention as a potential drug target in type 2 diabetes. This has in particular been spurred by the finding that PTP1B knockout mice show increased insulin sensitivity and resistance to diet-induced obesity. Surprisingly, the highly homologous T cell protein-tyrosine phosphatase (TC-PTP) has received much less attention, and no x-ray structure has been provided. We have previously co-crystallized PTP1B with a number of low molecular weight inhibitors that inhibit TC-PTP with similar efficiency. Unexpectedly, we were not able to co-crystallize TC-PTP with the same set of inhibitors. This seems to be due to a multimerization process where residues 130-132, the DDQ loop, from one molecule is inserted into the active site of the neighboring molecule, resulting in a continuous string of interacting TC-PTP molecules. Importantly, despite the high degree of functional and structural similarity between TC-PTP and PTP1B, we have been able to identify areas close to the active site that might be addressed to develop selective inhibitors of each enzyme. 相似文献
68.
Teresa E Clarke Volkmar Braun Gunther Winkelmann Leslie W Tari Hans J Vogel 《The Journal of biological chemistry》2002,277(16):13966-13972
Siderophore-binding proteins play an essential role in the uptake of iron in many Gram-positive and Gram-negative bacteria. FhuD is an ATP-binding cassette-type (ABC-type) binding protein involved in the uptake of hydroxamate-type siderophores in Escherichia coli. Structures of FhuD complexed with the antibiotic albomycin, the fungal siderophore coprogen and the drug Desferal have been determined at high resolution by x-ray crystallography. FhuD has an unusual bilobal structure for a periplasmic ligand binding protein, with two mixed beta/alpha domains connected by a long alpha-helix. The binding site for hydroxamate-type ligands is composed of a shallow pocket that lies between these two domains. Recognition of siderophores primarily occurs through interactions between the iron-hydroxamate centers of each siderophore and the side chains of several key residues in the binding pocket. Rearrangements of side chains within the binding pocket accommodate the unique structural features of each siderophore. The backbones of the siderophores are not involved in any direct interactions with the protein, demonstrating how siderophores with considerable chemical and structural diversity can be bound by FhuD. For albomycin, which consists of an antibiotic group attached to a hydroxamate siderophore, electron density for the antibiotic portion was not observed. Therefore, this study provides a basis for the rational design of novel bacteriostatic agents, in the form of siderophore-antibiotic conjugates that can act as "Trojan horses," using the hydroxamate-type siderophore uptake system to actively deliver antibiotics directly into targeted pathogens. 相似文献
69.
Nargang FE Preuss M Neupert W Herrmann JM 《The Journal of biological chemistry》2002,277(15):12846-12853
The Oxa1 protein is a ubiquitous constituent of the inner membrane of mitochondria. Oxa1 was identified in yeast as a crucial component of the protein export machinery known as the OXA translocase, which facilitates the integration of proteins from the mitochondrial matrix into the inner membrane. We have identified the Neurospora crassa Oxa1 protein which shows a sequence identity of 22% to the yeast homologue. Despite the low level of identity, the function of the homologues is conserved as the N. crassa gene fully complemented a yeast null mutant. Genetic analysis revealed that Oxa1 is essential for viability in N. crassa. Cells propagated under conditions that severely reduce Oxa1 levels grew extremely slowly and were deficient in subunits of complex I and complex IV. Isolation of the Oxa1 complex from N. crassa mitochondria revealed a 170-180-kDa complex that contained exclusively Oxa1. Since the Oxa1 monomer has a molecular weight of 43,000, our data suggest that the OXA translocase consists of a homooligomer most likely containing four Oxa1 subunits. 相似文献
70.