全文获取类型
收费全文 | 172篇 |
免费 | 19篇 |
出版年
2021年 | 4篇 |
2019年 | 2篇 |
2017年 | 1篇 |
2016年 | 5篇 |
2014年 | 4篇 |
2013年 | 6篇 |
2012年 | 1篇 |
2011年 | 9篇 |
2010年 | 6篇 |
2009年 | 2篇 |
2008年 | 5篇 |
2007年 | 9篇 |
2006年 | 15篇 |
2005年 | 7篇 |
2004年 | 9篇 |
2003年 | 15篇 |
2002年 | 16篇 |
2001年 | 7篇 |
2000年 | 7篇 |
1999年 | 4篇 |
1998年 | 2篇 |
1996年 | 2篇 |
1995年 | 1篇 |
1993年 | 1篇 |
1992年 | 2篇 |
1991年 | 4篇 |
1990年 | 2篇 |
1989年 | 1篇 |
1988年 | 3篇 |
1987年 | 4篇 |
1986年 | 5篇 |
1985年 | 5篇 |
1981年 | 1篇 |
1979年 | 1篇 |
1977年 | 1篇 |
1975年 | 3篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1961年 | 1篇 |
1959年 | 1篇 |
1957年 | 2篇 |
1956年 | 1篇 |
1954年 | 1篇 |
1952年 | 2篇 |
1943年 | 1篇 |
1940年 | 1篇 |
1926年 | 1篇 |
1924年 | 1篇 |
1922年 | 1篇 |
1921年 | 2篇 |
排序方式: 共有191条查询结果,搜索用时 774 毫秒
121.
Craven RA Hanrahan S Totty N Harnden P Stanley AJ Maher ER Harris AL Trimble WS Selby PJ Banks RE 《Proteomics》2006,6(13):3880-3893
The von Hippel Lindau (VHL) tumour suppressor gene, VHL, plays a central role in development of sporadic conventional renal cell carcinomas (RCCs). Studying VHL function may, therefore, increase understanding of the pathogenesis of RCC and identify markers/therapeutic targets. Comparison of 2-DE protein profiles of VHL-defective RCC cells (UMRC2) transfected with control vector or wild-type VHL showed differences in 30 proteins, including several novel changes. One of the findings confirmed by Western blotting was up-regulation of the mitochondrial protein ubiquinol cytochrome c reductase complex core protein 2 following VHL transfection, a change that was also observed in two other cell line backgrounds. A marked decrease in expression of this and several other mitochondrial proteins was demonstrated in RCC tissues and using VHL-transfectants, several were shown to exhibit VHL-dependent regulation. Thus, VHL may contribute to the decreased mitochondrial function seen in RCC. A form of septin 2 down-regulated following VHL transfection was also identified. Septin 2 was up-regulated in 12/16 RCCs, while alteration of the form present was also observed in 1/3 tumours analysed. Thus, increased expression of septin 2 is a common event in RCC and protein modification may also alter septin 2 function in a subset of tumours. 相似文献
122.
123.
124.
Pierre L. Beaulieu René Coulombe Jianmin Duan Gulrez Fazal Cédrickx Godbout Oliver Hucke Araz Jakalian Marc-André Joly Olivier Lepage Montse Llinàs-Brunet Julie Naud Martin Poirier Nathalie Rioux Bounkham Thavonekham George Kukolj Timothy A. Stammers 《Bioorganic & medicinal chemistry letters》2013,23(14):4132-4140
We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50 <200 nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B–ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors. 相似文献
125.
D K Stammers A Achari D O Somers P K Bryant J Rosemond D L Scott J N Champness 《FEBS letters》1999,456(1):49-53
The X-ray crystal structure of 7,8-dihydro-6-hydroxymethylpterinpyrophosphokinase (PPPK) in a ternary complex with ATP and a pterin analogue has been solved to 2.0 A resolution, giving, for the first time, detailed information of the PPPK/ATP intermolecular interactions and the accompanying conformational change. The first 100 residues of the 158 residue peptide contain a betaalpha betabeta alphabeta motif present in several other proteins including nucleoside diphosphate kinase. Comparative sequence examination of a wide range of prokaryotic and lower eukaryotic species confirms the conservation of the PPPK active site, indicating the value of this de novo folate biosynthesis pathway enzyme as a potential target for the development of novel broad-spectrum anti-infective agents. 相似文献
126.
127.
Bird LE Ren J Zhang J Foxwell N Hawkins AR Charles IG Stammers DK 《Structure (London, England : 1993)》2002,10(12):1687-1696
Prokaryotic genes related to the oxygenase domain of mammalian nitric oxide synthases (NOSs) have recently been identified. Although they catalyze the same reaction as the eukaryotic NOS oxygenase domain, their biological function(s) are unknown. In order to explore rationally the biochemistry and evolution of the prokaryotic NOS family, we have determined the crystal structure of SANOS, from methicillin-resistant Staphylococcus aureus (MRSA), to 2.4 A. Haem and S-ethylisothiourea (SEITU) are bound at the SANOS active site, while the intersubunit site, occupied by the redox cofactor tetrahydrobiopterin (H(4)B) in mammalian NOSs, has NAD(+) bound in SANOS. In common with all bacterial NOSs, SANOS lacks the N-terminal extension responsible for stable dimerization in mammalian isoforms, but has alternative interactions to promote dimer formation. 相似文献
128.
Sharpe BK Matthews JM Kwan AH Newton A Gell DA Crossley M Mackay JP 《Structure (London, England : 1993)》2002,10(5):639-648
Many different zinc binding modules have been identified. Their abundance and variety suggests that the formation of zinc binding folds might be relatively common. We have determined the structure of CH1(1), a 27-residue peptide derived from the first cysteine/histidine-rich region (CH1) of CREB binding protein (CBP). This peptide forms a highly ordered zinc-dependent fold that is distinct from known folds. The structure differs from a subsequently determined structure of a larger region from the CH3 region of CBP, and the CH1(1) fold probably represents a nonphysiologically active form. Despite this, the fold is thermostable and tolerant to both multiple alanine mutations and changes in the zinc-ligand spacing. Our data support the idea that zinc binding domains may arise frequently. Additionally, such structures may prove useful as scaffolds for protein design, given their stability and robustness. 相似文献
129.
Stevens DA Harvey CB Scott AJ O'Shea PJ Barnard JC Williams AJ Brady G Samarut J Chassande O Williams GR 《Molecular endocrinology (Baltimore, Md.)》2003,17(9):1751-1766
Thyroid hormone (T3) and the T3 receptor (TR) alpha gene are essential for bone development whereas adult hyperthyroidism increases the risk of osteoporotic fracture. We isolated fibroblast growth factor receptor-1 (FGFR1) as a T3-target gene in osteoblasts by subtraction hybridization. FGFR1 mRNA was induced 2- to 3-fold in osteoblasts treated with T3 for 6-48 h, and FGFR1 protein was stimulated 2- to 4-fold. Induction of FGFR1 was independent of mRNA half-life and abolished by actinomycin D and cycloheximide, indicating the involvement of an intermediary protein. Fibroblast growth factor 2 (FGF2) stimulated MAPK in osteoblasts, and pretreatment with T3 for 6 h induced a more rapid response to FGF that was increased in magnitude by 2- to 3-fold. Similarly, T3 enhanced FGF2-activated autophosphorylation of FGFR1, but did not modify FGF2-induced phosphorylation of the docking protein FRS2. These effects were abolished by the FGFR-selective inhibitors PD166866 and PD161570. In situ hybridization analyses of TRalpha-knockout mice, which have impaired ossification and skeletal mineralization, revealed reduced FGFR1 mRNA expression in osteoblasts and osteocytes, whereas T3 failed to stimulate FGFR1 mRNA or enhance FGF2-activated MAPK signaling in TRalpha-null osteoblasts. These findings implicate FGFR1 signaling in T3-dependent bone development and the pathogenesis of skeletal disorders resulting from thyroid disease. 相似文献
130.
Crystal structures of Zidovudine- or Lamivudine-resistant human immunodeficiency virus type 1 reverse transcriptases containing mutations at codons 41, 184, and 215 总被引:6,自引:0,他引:6
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Chamberlain PP Ren J Nichols CE Douglas L Lennerstrand J Larder BA Stuart DI Stammers DK 《Journal of virology》2002,76(19):10015-10019