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51.
Katarina Koruza Brian P. Mahon Matthew P. Blakeley Andreas Ostermann Tobias E. Schrader Robert McKenna Wolfgang Knecht S. Zoë Fisher 《Journal of structural biology》2019,205(2):147-154
Up-regulation of carbonic anhydrase IX (CA IX) expression is an indicator of metastasis and associated with poor cancer patient prognosis. CA IX has emerged as a cancer drug target but development of isoform-specific inhibitors is challenging due to other highly conserved CA isoforms. In this study, a CA IXmimic construct was used (CA II with seven point mutations introduced, to mimic CA IX active site) while maintaining CA II solubility that make it amenable to crystallography. The structures of CA IXmimic unbound and in complex with saccharin (SAC) and a saccharin-glucose conjugate (SGC) were determined using joint X-ray and neutron protein crystallography. Previously, SAC and SGC have been shown to display CA isoform inhibitor selectivity in assays and X-ray crystal structures failed to reveal the basis of this selectivity. Joint X-ray and neutron crystallographic studies have shown active site residues, solvent, and H-bonding re-organization upon SAC and SGC binding. These observations highlighted the importance of residues 67 (Asn in CA II, Gln in CA IX) and 130 (Asp in CA II, Arg in CA IX) in selective CA inhibitor targeting. 相似文献
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53.
Small molecule rescue of mutant forms of human carbonic anhydrase II (HCA II) occurs by participation of exogenous donors/acceptors in the proton transfer pathway between the zinc-bound water and solution. To examine more thoroughly the energetics of this activation, we have constructed a mutant, H64W HCA II, which we have shown is activated by 4-methylimidazole (4-MI) by a mechanism involving the binding of 4-MI to the side chain of Trp-64 approximately 8 A from the zinc. A series of experiments are consistent with the activation of H64W HCA II by the interaction of imidazole and pyridine derivatives as exogenous proton donors with the indole ring of Trp-64; these experiments include pH profiles and H/D solvent isotope effects consistent with proton transfer, observation of approximately fourfold greater activation with the mutant containing Trp-64 compared with Gly-64, and the observation by x-ray crystallography of the binding of 4-MI associated with the indole side chain of Trp-64 in W5A-H64W HCA II. Proton donors bound at the less flexible side chain of Trp-64 in W5A-H64W HCA II do not show activation, but such donors bound at the more flexible Trp-64 of H64W HCA II do show activation, supporting suggestions that conformational mobility of the binding site is associated with more efficient proton transfer. Evaluation using Marcus theory showed that the activation of H64W HCA II by these proton donors was reflected in the work functions w(r) and w(p) rather than in the intrinsic Marcus barrier itself, consistent with the role of solvent reorganization in catalysis. 相似文献
54.
55.
PHILIP S WANG MATTHIAS ANGERMEYER GUILHERME BORGES RONNY BRUFFAERTS WAI TAT CHIU GIOVANNI DE GIROLAMO JOHN FAYYAD OYE GUREJE JOSEP MARIA HARO YUEQIN HUANG RONALD C KESSLER VIVIANE KOVESS DAPHNA LEVINSON YOSHIBUMI NAKANE MARK A OAKLEY BROWN JOHAN H ORMEL JOSé POSADA-VILLA SERGIO AGUILAR-GAXIOLA JORDI ALONSO SING LEE STEVEN HEERINGA BETH-ELLEN PENNELL SOMNATH CHATTERJI T. BEDIRHAN üSTüN 《World psychiatry》2007,6(3):177-185
Data are presented on patterns of failure and delay in making initial treatment
contact after first onset of a mental disorder in 15 countries in the World
Health Organization (WHO)''s World Mental Health (WMH) Surveys. Representative
face-to-face household surveys were conducted among 76,012 respondents aged
18 and older in Belgium, Colombia, France, Germany, Israel, Italy, Japan,
Lebanon, Mexico, the Netherlands, New Zealand, Nigeria, People''s Republic
of China (Beijing and Shanghai), Spain, and the United States. The WHO Composite
International Diagnostic Interview (CIDI) was used to assess lifetime DSM-IV
anxiety, mood, and substance use disorders. Ages of onset for individual disorders
and ages of first treatment contact for each disorder were used to calculate
the extent of failure and delay in initial help seeking. The proportion of
lifetime cases making treatment contact in the year of disorder onset ranged
from 0.8 to 36.4% for anxiety disorders, from 6.0 to 52.1% for mood disorders,
and from 0.9 to 18.6% for substance use disorders. By 50 years, the proportion
of lifetime cases making treatment contact ranged from 15.2 to 95.0% for anxiety
disorders, from 7.9 to 98.6% for mood disorders, and from 19.8 to 86.1% for
substance use disorders. Median delays among cases eventually making contact
ranged from 3.0 to 30.0 years for anxiety disorders, from 1.0 to 14.0 years
for mood disorders, and from 6.0 to 18.0 years for substance use disorders.
Failure and delays in treatment seeking were generally greater in developing
countries, older cohorts, men, and cases with earlier ages of onset. These
results show that failure and delays in initial help seeking are pervasive
problems worldwide. Interventions to ensure prompt initial treatment contacts
are needed to reduce the global burdens and hazards of untreated mental disorders. 相似文献
56.
57.
58.
Duda D Tu C Qian M Laipis P Agbandje-McKenna M Silverman DN McKenna R 《Biochemistry》2001,40(6):1741-1748
Histidine 64 in human carbonic anhydrase II (HCA II) functions in the catalytic pathway of CO(2) hydration as a shuttle to transfer protons between the zinc-bound water and bulk water. Catalysis of the exchange of (18)O between CO(2) and water, measured by mass spectrometry, is dependent on this proton transfer and was decreased more than 10-fold for H64A HCA II compared with wild-type HCA II. The loss of catalytic activity of H64A HCA II could be rescued by 4-methylimidazole (4-MI), an exogenous proton donor, in a saturable process with a maximum activity of 40% of wild-type HCA II. The crystal structure of the rescued complex at 1.6 A resolution shows 4-MI bound in the active-site cavity of H64A HCA II, through pi stacking interactions with Trp 5 and H-bonding interactions with water molecules. In this location, 4-MI is about 12 A from the zinc and approximates the observed "out" position of His 64 in the structure of the wild-type enzyme. 4-MI appears to compensate for the absence of His 64 and rescues the catalytic activity of the H64A HCA II mutant. This result strongly suggests that the out conformation of His 64 is effective in the transfer of protons between the zinc-bound solvent molecule and solution. 相似文献
59.
Profilin inhibits pollen tube growth through actin-binding,but not poly-<Emphasis Type="SmallCaps">l</Emphasis>-proline-binding 总被引:3,自引:0,他引:3
Previously, we have shown that excess profilin inhibits pollen tube growth at significantly lower concentrations than it blocks cytoplasmic streaming. To elucidate the mechanism by which profilin achieves this function, we have employed mutant profilins from Schizosaccharomyces pombe [J. Lu and T.D. Pollard (2001) Mol Biol Cell 12:1161–1175], which have defects in actin-binding, ability to inhibit polymerization, and poly-l-proline (PLP)-binding. Using Lilium longiflorum L. pollen and S. pombe profilins as wild-type (wt) standards, mutant profilins have been injected into pollen tubes of Lilium, and examined for their effects on growth rate and cell morphology. Our results show that mutant Y5D (68% actin-binding; 1.1% PLP-binding) is indistinguishable from wt-standard profilins. However mutant K81F (2.7% actin-binding; 77% PLP-binding) and especially mutant K67E (<1% actin-binding; 100% PLP-binding) are significantly less effective than wt-standard profilins in their ability to inhibit pollen tube growth. PLP also inhibits pollen tube growth. However, PLP is not different from K67E/PLP combined, which has no actin-binding, suggesting that PLP does not function by binding to profilin. In addition, there are differences in the morphology and F-actin organization in cells injected with PLP versus wt-profilin. Whereas wt-profilin causes a fragmentation and marked reduction in the amount of F-actin [L. Vidali et al. (2001) Mol Biol Cell 12:2534–2545], PLP generates an extensive disorganization without any apparent reduction in the amount of F-actin. We conclude that along with actin-binding activity of profilin, PLP-containing proteins also participate in the growth control process, and can do so independently of binding to profilin.Abbreviations
3D
Three-dimensional
-
PLP
Poly-l-proline
-
RMS
Root mean square
-
wt
Wild type 相似文献
60.
Govindasamy L Kukar T Lian W Pedersen B Gu Y Agbandje-McKenna M Jin S McKenna R Wu D 《Journal of structural biology》2004,146(3):416-424
We report the crystal structure of a binary complex of human peroxisomal carnitine acetyltransferase and the substrate l-carnitine, refined to a resolution of 1.8 Angstrom with an R(factor) value of 18.9% (R(free)=22.3%). L-carnitine binds to a preformed pocket in the active site tunnel of carnitine acetyltransferase aligned with His(322). The quaternary nitrogen of carnitine forms a pi-cation interaction with Phe(545), while Arg(497) forms an electrostatic interaction with the negatively charged carboxylate group. An extensive hydrogen bond network also occurs between the carboxylate group and Tyr(431), Thr(444), and a bound water molecule. Site-directed mutagenesis and kinetic characterization reveals that Tyr(431), Thr(444), Arg(497), and Phe(545) are essential for high affinity binding of L-carnitine. 相似文献