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121.
Versha Rai Antresh Kumar Sneha Sudha Komath Rajendra Prasad 《生物化学与生物物理学报:生物膜》2008,1778(10):2143-2153
Although essentially conserved, the N-terminal nucleotide-binding domain (NBD) of Cdr1p and other fungal transporters has some unique substitutions of amino acids which appear to have functional significance for the drug transporters. We have previously shown that the typical Cys193 in Walker A as well as Trp326 and Asp327 in the Walker B of N-terminal NBD (NBD-512) of Cdr1p has acquired unique roles in ATP binding and hydrolysis. In the present study, we show that due to spatial proximity, fluorescence resonance energy transfer (FRET) takes place between Trp326 of Walker B and MIANS [2-(4-maleimidoanilino) naphthalene-6-sulfonic acid] on Cys193 of Walker A motif. By exploiting FRET, we demonstrate how these critical amino acids are positioned within the nucleotide-binding pocket of NBD-512 to bind and hydrolyze ATP. Our results show that both Mg2+ coordination and nucleotide binding contribute to the formation of the active site. The entry of Mg2+ into the active site causes the first large conformational change that brings Trp326 and Cys193 in close proximity to each other. We also show that besides Trp326, typical Glu238 in the Q-loop also participates in coordination of Mg2+ by NBD-512. A second conformational change is induced when ATP, but not ADP, docks into the pocket. Asn328 does sensing of the γ-phosphate of the substrate in the extended Walker B motif, which is essential for the second conformational change that must necessarily precede ATP hydrolysis. Taken together our results imply that the uniquely placed residues in NBD-512 have acquired critical roles in ATP catalysis, which drives drug extrusion. 相似文献
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The breast and ovarian cancer suppressor protein BRCA2 controls the RAD51 recombinase in reactions that lead to homologous DNA recombination (HDR). BRCA2 binds RAD51 via eight conserved BRC repeat motifs of approximately 35 amino acids, each with a varying capacity to bind RAD51. BRC repeats both promote and inhibit RAD51 assembly on different DNA substrates to regulate HDR, but the structural basis for these functions is unclear. Here, we demarcate two tetrameric clusters of hydrophobic residues in the BRC repeats, interacting with distinct pockets in RAD51, and show that the co-location of both modules within a single BRC repeat is necessary for BRC–RAD51 binding and function. The two modules comprise the sequence FxxA, known to inhibit RAD51 assembly by blocking the oligomerization interface, and a previously unrecognized tetramer with the consensus sequence LFDE, which binds to a RAD51 pocket distinct from this interface. The LFDE motif is essential in BRC repeats for modes of RAD51 binding both permissive and inhibitory to RAD51 oligomerization. Targeted insertion of point mutations in RAD51 that disrupt the LFDE-binding pocket impair its assembly at DNA damage sites in living cells. Our findings suggest a model for the modular architecture of BRC repeats that provides fresh insight into the mechanisms regulating homologous DNA recombination. 相似文献
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Karl Deacon David Onion Rajendra Kumari Susan A. Watson Alan J. Knox 《The Journal of biological chemistry》2012,287(47):39967-39981
127.
Wighart von Koenigswald Kenneth D. Rose Luke T. Holbrook Kishor Kumar Rajendra S. Rana Thierry Smith 《Pal?ontologische Zeitschrift》2018,92(4):671-680
The dentition of Cambaytherium was investigated in terms of dental wear, tooth replacement and enamel microstructure. The postcanine tooth row shows a significant wear gradient, with flattened premolars and anterior molars at a time when the last molars are only little worn. This wear gradient, which is more intensive in Cambaytherium thewissi than in Cambaytherium gracilis, and the resulting flattened occlusal surfaces, may indicate a preference for a durophagous diet. The tooth replacement (known only in C. thewissi) shows an early eruption of the permanent premolars. They are in function before the third molars are fully erupted. During the dominant phase I of the chewing cycle the jaw movement is very steep, almost orthal, with a slight mesiolingual direction and changes into a horizontal movement during phase II. The enamel microstructure shows Hunter-Schreger-bands (HSB) in the inner zone of the enamel. In some teeth the transverse orientation of the HSB is modified into a zig-zag pattern, possibly an additional indicator of a durophagous diet. 相似文献
128.
Shradha Bahuguna Manish Kumar Gajanand Sharma Rajendra Kumar Bhupinder Singh Kaisar Raza 《AAPS PharmSciTech》2018,19(3):1084-1092
Derivatization of fullerenes to polyhydroxylated fullerenes, i.e., fullerenols (FLU), dramatically decreases their toxicity and has been reported to enhance the solubility as well as cellular permeability. In this paper, we report synthesis of FLU as nanocarrier and subsequent chemical conjugation of Methotrexate (MTX) to FLU with a serum-stable and intracellularly hydrolysable ester bond between FLU and MTX. The conjugate was characterized for physiochemical attributes, micromeritics, drug-loading, and drug-release and evaluated for cancer cell-toxicity, cellular-uptake, hemocompatibility, protein binding, and pharmacokinetics. The developed hemocompatible FL-MTX offered lower protein binding vis-à-vis naïve drug and substantially higher drug loading. The conjugate offered pH-dependent release of 38.20?±?1.19% at systemic pH and 85.67?±?3.39% at the cancer cell pH. FLU-MTX-treated cells showed significant reduction in IC50 value vis-à-vis the cells treated with pure MTX. Analogously, the results from confocal scanning laser microscopy also confirmed the easy access of the dye-tagged FLU-MTX conjugate to the cell interiors. In pharmacokinetics, the AUC of MTX was enhanced by approx. 6.15 times and plasma half-life was enhanced by 2.45 times, after parenteral administration of single equivalent dose in rodents. FLU-MTX offered enhanced availability of drug to the biological system, meanwhile improved the cancer-cell cytotoxicity, sustained the effective plasma drug concentrations, and offered substantial compatibility to erythrocytes. 相似文献
129.
Singh Rajendra Pandey Deepak Devi Neena Chand Duni 《Bioprocess and biosystems engineering》2018,41(8):1225-1232
Bioprocess and Biosystems Engineering - Butyramide is a commodity chemical having wide range of applications from material science to biological sciences including synthesis of therapeutic drugs,... 相似文献
130.
The recent advancement in new generation fluorinated pyrethroids (e.g., transfluthrin, metofluthrin etc.), the use of semi-volatile vapour phase insecticides for control of mosquitoes and other domestic pests rises. Enabling the examination of the vapour toxicity profiles of these molecules and many other similar new generation molecules will provide new avenues for researchers for understanding the bio-potency in the spatial killing of pests. Hence, it is critical to establish a well-controlled portable vapour-phase bioassay method that can provide the desired precision, accuracy, linearity and robustness. In this respect, we have designed a vapour-toxicity apparatus comprising glass assemblies and developed a novel bioassay method. We found that KT50 and percentage knockdown at 60?min reflect the concentration dependency. This validates and confirms that the method is sensitive enough to distinguish between concentrations and suitable for concentration-response experiments. We found that KT50 and percentage knockdown at 60?min at a given concentration does not differ significantly between experiments. Hence, the method has repeatability and precision. Percentage mortality and total KT50 against Culex quinquefasciatus shows that percentage mortality increases and KT50 decreases linearly with the increasing concentration. This method provides an easy to operate tool to test the vapour toxicity profiles of any vapour phase insecticide molecules against mosquitoes and flying insects. 相似文献