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61.
Justin Dietrich Vijay Gokhale Xiadong Wang Laurence H. Hurley Gary A. Flynn 《Bioorganic & medicinal chemistry》2010,18(1):292-304
B-Raf protein kinase, which is a key signaling molecule in the RAS–RAF–MEK–ERK signaling pathway, plays an important role in many cancers. The B-Raf V600E mutation represents the most frequent oncogenic kinase mutation known and is responsible for increased kinase activity in approximately 7% of all human cancers, establishing B-Raf as an important therapeutic target for inhibition. Through the use of an iterative program that utilized a chemocentric approach and a rational structure based design, we have developed novel, potent, and specific DFG-out allosteric inhibitors of B-Raf kinase. Here, we present efficient and versatile chemistry that utilizes a key one pot, [3+2] cycloaddition reaction to obtain highly substituted imidazoles and their application in the design of allosteric B-Raf inhibitors. Inhibitors based on this scaffold display subnanomolar potency and a favorable kinase profile. 相似文献
62.
Gokhale NA Abraham A Digman MA Gratton E Cho W 《The Journal of biological chemistry》2005,280(52):42831-42840
Annexin A2 is a phospholipid-binding protein that forms a heterotetramer (annexin II-p11 heterotetramer; A2t) with p11 (S100A10). It has been reported that annexin A2 is involved in binding to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and in inducing membrane microdomain formation. To understand the mechanisms underlying these findings, we determined the membrane binding properties of annexin A2 wild type and mutants both as monomer and as A2t. Our results from surface plasmon resonance analysis showed that A2t and annexin A2 has modest selectivity for PtdIns(4,5)P2 over other phosphoinositides, which is conferred by conserved basic residues, including Lys279 and Lys281, on the convex surface of annexin A2. Fluorescence microscopy measurements using giant unilamellar vesicles showed that A2t of wild type, but not (K279A)2-(p11)2 or (K281A)2-(p11)2, specifically induced the formation of 1-microm-sized PtdIns(4,5)P2 clusters, which were stabilized by cholesterol. Collectively, these studies elucidate the structural determinant of the PtdIns(4,5)P2 selectivity of A2t and suggest that A2t may be involved in the regulation of PtdIns(4,5)P2 clustering in the cell. 相似文献
63.
India has a unique opportunity to become a leader in biological sciences research. In this commentary, we address what India needs to do to achieve this goal. 相似文献
64.
Gokhale KC Newnam GP Sherman MY Chernoff YO 《The Journal of biological chemistry》2005,280(24):22809-22818
In yeast, aggregation and toxicity of the expanded polyglutamine fragment of human huntingtin strictly depend on the presence of the endogenous self-perpetuating aggregated proteins (prions), which contain glutamine/asparagine-rich domains. Some chaperones of the Hsp100/70/40 complex, modulating propagation of yeast prions, were also reported to influence polyglutamine aggregation in yeast, but it was not clear whether they do it directly or via affecting prions. Our data show that although some chaperone alterations indeed act on polyglutamines via curing endogenous prions, other alterations decrease size and ameliorate toxicity of polyglutamine aggregates without affecting prion propagation. Therefore, the role of yeast chaperones in polyglutamine aggregation and toxicity is not restricted only to their effects on the endogenous prions. Moreover, chaperone interactions with prion and polyglutamine aggregates appear to be of a highly specific nature. One and the same chaperone alteration, substitution A503V in the middle region of the chaperone Hsp104, exhibited opposite effects on one of the endogenous prions ([PSI(+)], the prion form of Sup35) and on polyglutamines, increasing aggregate size and toxicity in the former case and decreasing them in the latter case. On the other hand, different members of a single chaperone family exhibited opposite effects on one and the same type of aggregates: excess of the Hsp40 chaperone Ydj1 increased polyglutamine aggregate size and toxicity, whereas excess of the other Hsp40 chaperone, Sis1, decreased them. As many stress-defense proteins are conserved between yeast and mammals, these data shed light on possible mechanisms modulating polyglutamine aggregation and toxicity in mammalian cells. 相似文献
65.
Michael?B?Kupper Michael?Huhn Holger?Spiegel Julian?KC?Ma Stefan?Barth Rainer?Fischer Ricarda?FinnernEmail author 《BMC biotechnology》2005,5(1):4
Background
Common oral diseases and dental caries can be prevented effectively by passive immunization. In humans, passive immunotherapy may require the use of humanized or human antibodies to prevent adverse immune responses against murine epitopes. Therefore we generated human single chain and diabody antibody derivatives based on the binding characteristics of the murine monoclonal antibody Guy's 13. The murine form of this antibody has been used successfully to prevent Streptococcus mutans colonization and the development of dental caries in non-human primates, and to prevent bacterial colonization in human clinical trials. 相似文献66.
Sankaranarayanan R Saxena P Marathe UB Gokhale RS Shanmugam VM Rukmini R 《Nature structural & molecular biology》2004,11(9):894-900
The superfamily of plant and bacterial type III polyketide synthases (PKSs) produces diverse metabolites with distinct biological functions. PKS18, a type III PKS from Mycobacterium tuberculosis, displays an unusual broad specificity for aliphatic long-chain acyl-coenzyme A (acyl-CoA) starter units (C(6)-C(20)) to produce tri- and tetraketide pyrones. The crystal structure of PKS18 reveals a 20 A substrate binding tunnel, hitherto unidentified in this superfamily of enzymes. This remarkable tunnel extends from the active site to the surface of the protein and is primarily generated by subtle changes of backbone dihedral angles in the core of the protein. Mutagenic studies combined with structure determination provide molecular insights into the structural elements that contribute to the chain length specificity of the enzyme. This first bacterial type III PKS structure underlines a fascinating example of the way in which subtle changes in protein architecture can generate metabolite diversity in nature. 相似文献
67.
Mourya DT Gokhale MD Barde PV Deobagkar DN 《Indian journal of experimental biology》2001,39(8):807-810
Insecticide bioassays were carried out on larvae and adults of rosy eye mutant and wildtype strains of A. aegypti. Both the strains were equally susceptible to DDT, malathion and deltamethrin. Biochemical assays showed an increase in acetylcholinesterase enzyme (AChE) activity in all the stages of mutant strain with both the substrates i.e. acetylthiocholine iodide and S-butyrylthiocholine iodide. However, there was no difference in the percent inhibition of enzyme activity with propoxur in these two strains. Polyacrylamide gel electrophoresis performed in native conditions on the homogenates of adults of rosy eye mosquitoes showed that AChE-II allele was highly active with the substrate acetylthiocholine iodide as compared to wildtype strain. Frequency of the highly active AChE-II allele in the mutant strain was about 68%, whereas it was about 5% in the wildtype strain. 相似文献
68.
The advent of Massively Parallel Network of Workstations (MP-NOW) represents an important trend in high performance computing.
The rise of interpreted languages (e.g., Visual Basic, MATLAB, IDL, Maple and Mathematica) for algorithm development, prototyping,
data analysis and graphical user interfaces (GUIs) represents an important trend in software engineering. However, using interpreted
languages on a MP-NOW is a significant challenge. We present a specific example of a very simple, but generic solution to
this problem. Our example uses an interpreted language to set up a calculation and then interfaces with a computational kernel
written in a compiled language (e.g., C, C++, Fortran). The interpreted language calls the computational kernel as an external
library. We have added to the computational kernel an additional layer, which manages multiple copies of the kernel running
on a MP-NOW and returns the results back to the interpreted layer. Our implementation uses The Next generation Taskbag (TNT)
library developed at Sarnoff to provide an efficient means for implementing task parallelism. A test problem (taken from Astronomy)
has been implemented on the Sarnoff Cyclone computer which consists of 160 heterogeneous nodes connected by a “fat” tree 100
Mb/s switched Ethernet running the RedHat Linux and FreeBSD operating systems. Our first results in this ongoing project have
demonstrated the feasibility of this approach and produced speedups of greater than 50 on 60 processors.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
69.
Zeyuan Song Tao Wu Jinpeng Sun Haoran Wang Feng Hua Yap San Min Nicolas Rupesh KC Kun Chen Zhen Jin Jun Liu Mingshun Zhang 《Journal of cellular and molecular medicine》2021,25(7):3272-3283
Excessive post-epidural fibrosis is a common cause of recurrent back pain after spinal surgery. Though various treatment methods have been conducted, the safe and effective drug for alleviating post-epidural fibrosis remains largely unknown. Metformin, a medicine used in the treatment of type 2 diabetes, has been noted to relieve fibrosis in various organs. In the present study, we aimed to explore the roles and mechanisms of metformin in scar formation in a mouse model of laminectomy. Post-epidural fibrosis developed in a mouse model of laminectomy by spinous process and the T12-L2 vertebral plate with a rongeur. With the administration of metformin, post-epidural fibrosis was reduced, accompanied with decreased collagen and fibronectin in the scar tissues. Mechanistically, metformin decreased fibronectin and collagen deposition in fibroblast cells, and this effect was dependent on the HMGB1/TLR4 and TGF-β1/Smad3 signalling pathways. In addition, metformin influenced the metabolomics of the fibroblast cells. Taken together, our study suggests that metformin may be a potential option to mitigate epidural fibrosis after laminectomy. 相似文献
70.