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91.
Varga B Barabás O Kovári J Tóth J Hunyadi-Gulyás E Klement E Medzihradszky KF Tölgyesi F Fidy J Vértessy BG 《FEBS letters》2007,581(24):4783-4788
Human dUTPase, essential for DNA integrity, is an important survival factor for cancer cells. We determined the crystal structure of the enzyme:alpha,beta-imino-dUTP:Mg complex and performed equilibrium binding experiments in solution. Ordering of the C-terminus upon the active site induces close juxtaposition of the incoming nucleophile attacker water oxygen and the alpha-phosphorus of the substrate, decreasing their distance below the van der Waals limit. Complex interactions of the C-terminus with both substrate and product were observed via a specifically designed tryptophan sensor, suitable for further detailed kinetic and ligand binding studies. Results explain the key functional role of the C-terminus. 相似文献
92.
The diffusion properties of EGFP-hGRalpha and mutants C421G, A458T and I566 in living cells were analyzed. The wild type and mutants C421G and A458T translocated from the cytoplasm to the nucleus after addition of Dex; however, the Brownian motions of the proteins were different. The diffusion constant of wild-type GRalpha after addition of Dex slowed to 15.6% of that in the absence of Dex, whereas those of A458T and C421G slowed to 34.8% and 61.7%, respectively. This is the first report that dimer formation is less important than the binding activity of GRalpha to GRE in the living cell. 相似文献
93.
94.
The prediction of the complex structure of a small ligand with a protein, the so-called protein–ligand docking problem, is
a central part of the rational drug design process. For this purpose, we introduce the docking algorithm PLANTS (Protein–Ligand
ANT System), which is based on ant colony optimization, one of the most successful swarm intelligence techniques. We study
the effectiveness of PLANTS for several parameter settings and present a direct comparison of PLANTS’s performance to a state-of-the-art
program called GOLD, which is based on a genetic algorithm and frequently used in the pharmaceutical industry for this task.
Last but not least, we also show that PLANTS can make effective use of protein flexibility giving example results on cross-docking and virtual screening experiments for protein kinase A.
This article is based on a paper that won the best paper award at ANTS 2006, the 5th International Workshop on Ant Colony
Optimization and Swarm Intelligence held in Brussels, Belgium, 2006. This article includes new types of experiments and also
the possibility of considering flexibility of protein side-chains. 相似文献
95.
Typical physico-chemical studies of metal binding proteins are usually aimed at determination of the metal binding constant
K for a native protein (K
n), while the significance of the K value for the thermally denatured protein (K
u) is usually underestimated. Meanwhile, metal binding induced shift of thermal denaturation transition of a single site metal
binding protein is defined by K
n to K
u ratio, implying that knowledge of both K values is required for full characterization of the system. In the present work, the most universal approach to the studies
of single site metal binding proteins, namely construction of a protein “phase diagram” in coordinates of free metal ion concentration
– temperature, is considered in detail. The detailed algorithm of construction of the phase diagrams along with underlying
mathematic procedures developed here may be of use for studies of other simple protein-target type systems, where target represents
low molecular weight ligand. Analysis of the simplest protein-ligand system reveals that thermodynamic properties of apo-protein
dictate the maximal possible increase of its affinity to any simple ligand upon thermal denaturation of the protein. Experimental
and general problems coupled with the use of the phase diagrams are discussed. 相似文献
96.
Zhi-Chao Yuan Jia-Min Wang Lin-Chong Su Wang-Dong Xu An-Fang Huang 《Journal of cellular physiology》2019,234(7):11760-11767
Recent findings showed elevated expression of tumor necrosis factor (TNF)-like ligand 1A (TL1A) in rheumatoid arthritis (RA) patients and arthritis mice. However, whether TL1A gene polymorphisms may correlate with RA susceptibility needs to be discussed. This case-control study was performed on 350 RA patients and 556 healthy subjects to identify TL1A genetic variants (rs3810936, rs6478109, and rs7848647) and their possible association with TL1A levels, susceptibility to and severity of RA. Odds ratio and 95% confidence interval were calculated to represent the correlation between TL1A polymorphisms and RA. The TL1A serum levels were evaluated. Results showed that frequencies of TC, TT + TC genotypes of rs3810936, rs7848647 in RA patients were significantly lower in RA patients compared with controls. Patients with C allele showed more severe disease course (disease activity index: erythrocyte sedimentation rate, rheumatoid factor) than in carriers of T allele. However, the allele or genotype frequencies of rs6478109 were not associated with RA. In addition, TL1A genetic variants conferred higher TL1A levels in RA patients compared with controls. In conclusion, these findings indicated an association between TL1A rs3810936, rs7848647 variation and the susceptibility of RA in a sample of Chinese individuals, and TL1A may correlate with severity of RA. 相似文献
97.
Initially understood for its physiological maintenance of self-tolerance, the immune checkpoint molecule has recently been recognized as a promising anti-cancer target. There has been considerable interest in the biology and the action mechanism of the immune checkpoint therapy, and their incorporation with other therapeutic regimens. Recently the small-molecule inhibitor (SMI) has been identified as an attractive combination partner for immune checkpoint inhibitors (ICIs) and is becoming a novel direction for the field of combination drug design. In this review, we provide a systematic discussion of the biology and function of major immune checkpoint molecules, and their interactions with corresponding targeting agents. With both preclinical studies and clinical trials, we especially highlight the ICI + SMI combination, with its recent advances as well as its application challenges. 相似文献
98.
Juergen Haas Rafal Gumienny Alessandro Barbato Flavio Ackermann Gerardo Tauriello Martino Bertoni Gabriel Studer Anna Smolinski Torsten Schwede 《Proteins》2019,87(12):1378-1387
Critical blind assessment of structure prediction techniques is crucial for the scientific community to establish the state of the art, identify bottlenecks, and guide future developments. In Critical Assessment of Techniques in Structure Prediction (CASP), human experts assess the performance of participating methods in relation to the difficulty of the prediction task in a biennial experiment on approximately 100 targets. Yet, the development of automated computational modeling methods requires more frequent evaluation cycles and larger sets of data. The “Continuous Automated Model EvaluatiOn (CAMEO)” platform complements CASP by conducting fully automated blind prediction evaluations based on the weekly pre-release of sequences of those structures, which are going to be published in the next release of the Protein Data Bank (PDB). Each week, CAMEO publishes benchmarking results for predictions corresponding to a set of about 20 targets collected during a 4-day prediction window. CAMEO benchmarking data are generated consistently for all methods at the same point in time, enabling developers to cross-validate their method's performance, and referring to their results in publications. Many successful participants of CASP have used CAMEO—either by directly benchmarking their methods within the system or by comparing their own performance to CAMEO reference data. CAMEO offers a variety of scores reflecting different aspects of structure modeling, for example, binding site accuracy, homo-oligomer interface quality, or accuracy of local model confidence estimates. By introducing the "bestSingleTemplate" method based on structure superpositions as a reference for the accuracy of 3D modeling predictions, CAMEO facilitates objective comparison of techniques and fosters the development of advanced methods. 相似文献
99.
Chirality plays a pivotal role in an uncountable number of biological processes, and nature has developed intriguing mechanisms to maintain this state of enantiopurity. The strive for a deeper understanding of the different elements that constitute such self‐sustaining systems on a molecular level has sparked great interest in the studies of autoinductive and amplifying enantioselective reactions. The design of these reactions remains highly challenging; however, the development of generally applicable principles promises to have a considerable impact on research of catalyst design and other adjacent fields in the future. Here, we report the realization of an autoinductive, enantioselective self‐inhibiting hydrogenation reaction. Development of a stereodynamic catalyst with chiral sensing abilities allowed for a chiral reaction product to interact with the catalyst and change its selectivity in order to suppress its formation, which caused a reversal of selectivity over time. 相似文献
100.
Zhenhua Pan Mengwen Zhao Yonglin Peng 《Journal of biomolecular structure & dynamics》2019,37(11):2938-2948
Nicotinic acetylcholine receptors (nAChRs) are pentamers formed by subunits from a large multigene family and are highly variable in kinetic, electrophysiological and pharmacological properties. Due to the essential roles of nAChRs in many physiological procedures and diversity in function, identifying the function-related sites specific to each subunit is not only necessary to understand the properties of the receptors but also useful to design potential therapeutic compounds that target these macromolecules for treating a series of central neuronal disorders. By conducting a detailed function divergence analysis on nine neuronal nAChR subunits from representative vertebrate species, we revealed the existence of significant functional variation between most subunit pairs. Specifically, 44 unique residues were identified for the α7 subunit, while another 22 residues that were likely responsible for the specific features of other subunits were detected. By mapping these sites onto the 3?D structure of the human α7 subunit, a structure-function relationship profile was revealed. Our results suggested that the functional divergence related sites clustered in the ligand binding domain, the β2–β3 linker close to the N-terminal α-helix, the intracellular linkers between transmembrane domains, and the “transition zone” may have experienced altered evolutionary rates. The former two regions may be potential binding sites for the α7* subtype-specific allosteric modulators, while the latter region is likely to be subtype-specific allosteric modulations of the heteropentameric descendants such as the α4β2* nAChRs.
Communicated by Ramaswamy H. Sarma 相似文献