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991.
Jinwal UK Abisambra JF Zhang J Dharia S O'Leary JC Patel T Braswell K Jani T Gestwicki JE Dickey CA 《The Journal of biological chemistry》2012,287(29):24814-24820
The RNA-binding protein, trans-active response DNA-binding protein 43 (TDP-43), is normally found in the nucleus, but in amyotrophic lateral sclerosis, frontal temporal dementia, and some cases of Alzheimer disease it is cleaved and mislocalized to the cytosol, leading to accumulation. The mechanisms contributing to this are largely unknown. Here, we show that part of the normal clearance cascade for TDP-43 involves the Cdc37/Hsp90 complex. An Hsp90 inhibitor that disrupts the Cdc37/Hsp90 complex reduced TDP-43 levels to a greater extent than a standard Hsp90 ATPase inhibitor. When Cdc37 was depleted, TDP-43 underwent proteolytic clearance that was dependent on nuclear retrotranslocation and autophagic uptake. Accumulation of the microtubule-associated protein tau prevented the clearance of cleaved TDP-43, but not its production. This caused cleaved TDP-43 to accumulate, a feature observed in the brain of persons with Alzheimer disease. Clearance of cleaved TDP-43 was also prevented by knockdown of the autophagic inducer beclin1. Thus, in cells where TDP-43 clearance is normally needed, a system that employs manipulation of the Hsp90 complex and autophagy exists. But when tau accumulation is occurring, cleaved TDP-43 can no longer be cleared, perhaps explaining the emergence of these co-pathologies. 相似文献
992.
Singh R Basera SS Tewari K Yadav S Joshi S Singh B Mukherjee F 《Indian journal of experimental biology》2012,50(3):239-242
Safety and immunogenicity of Brucella abortus RB51 vaccine has been evaluated in an organised dairy farm in India. All the cattle (r = 29) vaccinated with strain RB51 'responded' to the vaccine as demonstrated by iELISA using acetone killed strain RB51 antigen. The percentage responders at day 35, 60 and 90 post vaccination were 100%, 95% and 20%, respectively. Strain RB51 was able to elicit a good IFN-gamma response from vaccinated animals. The post-vaccination time point analysis indicated that the cumulative IFN-gamma response of whole blood from vaccinates stimulated with heat killed RB51 antigen was elicited in 80% of calves at 60 days post vaccination. Absence of strain RB51 in the secretions and excretion and lack of local or systemic reaction indicated the safety of the vaccine. 相似文献
993.
Human cystathionine β-synthase (CBS), a novel heme-containing pyridoxal 5′-phosphate enzyme, catalyzes the condensation of homocysteine and serine or cysteine to produce cystathionine and H2O or H2S, respectively. The presence of heme in CBS has limited spectrophotometric characterization of reaction intermediates by masking the absorption of the pyridoxal 5′-phosphate cofactor. In this study, we employed difference stopped-flow spectroscopy to characterize reaction intermediates formed under catalytic turnover conditions. The reactions of l-serine and l-cysteine with CBS resulted in the formation of a common aminoacrylate intermediate (kobs = 0.96 ± 0.02 and 0.38 ± 0.01 mm−1 s−1, respectively, at 24 °C) with concomitant loss of H2O and H2S and without detectable accumulation of the external aldimine or other intermediates. Homocysteine reacted with the aminoacrylate intermediate with kobs = 40.6 ± 3.8 s−1 and re-formed the internal aldimine. In the reverse direction, CBS reacted with cystathionine, forming the aminoacrylate intermediate with kobs = 0.38 ± 0.01 mm−1 s−1. This study provides the first insights into the pre-steady-state kinetic mechanism of human CBS and indicates that the reaction is likely to be limited by a conformational change leading to product release. 相似文献
994.
Oxana V. Denisova Laura Kakkola Lin Feng Jakob Stenman Ashwini Nagaraj Johanna Lampe Bhagwan Yadav Tero Aittokallio Pasi Kaukinen Tero Ahola Suvi Kuivanen Olli Vapalahti Anu Kantele Janne Tynell Ilkka Julkunen Hannimari Kallio-Kokko Henrik Paavilainen Veijo Hukkanen Richard M. Elliott Jef K. De Brabander Xavier Saelens Denis E. Kainov 《The Journal of biological chemistry》2012,287(42):35324-35332
995.
Suman Yadav Girish Sahni 《Biochimica et Biophysica Acta - Proteins and Proteomics》2010,1804(9):1730-1737
The bacterial protein streptokinase (SK) contains three independently folded domains (α, β and γ), interconnected by two flexible linkers with noticeable sequence homology. To investigate their primary structure requirements, the linkers were swapped amongst themselves i.e. linker 1 (between α and β domains) was swapped with linker 2 (between β and γ domains) and vice versa. The resultant construct exhibited very low activity essentially due to an enhanced proteolytic susceptibility. However, a SK mutant with two linker 1 sequences, which was proteolytically as stable as WT-rSK retained about 10% of the plasminogen activator activity of rSK When the native sequence of each linker was substituted with 9 consecutive glycine sequences, in case of the linker 1 substitution mutant substantial activity was seen to survive, whereas the linker 2 mutant lost nearly all its activity. The optimal length of linkers was then studied through deletion mutagenesis experiments, which showed that deletion beyond three residues in either of the linkers resulted in virtually complete loss of activator activity. The effect of length of the linkers was then also examined by insertion of extraneous pentapeptide sequences having a propensity for adopting either an extended conformation or a relatively rigid conformation. The insertion of poly-Pro sequences into native linker 2 sequence caused up to 10-fold reduction in activity, whereas its effect in linker 1 was relatively minor. Interestingly, most of the linker mutants could form stable 1:1 complexes with human plasminogen. Taken together, these observations suggest that (i) the functioning of the inter-domain linkers of SK requires a critical minimal length, (ii) linker 1 is relatively more tolerant to insertions and sequence alterations, and appears to function primarily as a covalent connector between the α and β domains, and (iii) the native linker 2 sequence is virtually indispensable for the activity of SK probably because of structural and/or flexibility requirements in SK action during catalysis. 相似文献
996.
Rohan Patil Suranjana Das Ashley Stanley Lumbani Yadav Akulapalli Sudhakar Ashok K. Varma 《PloS one》2010,5(8)
Background
Weak intermolecular interactions such as hydrogen bonding and hydrophobic interactions are key players in stabilizing energetically-favored ligands, in an open conformational environment of protein structures. However, it is still poorly understood how the binding parameters associated with these interactions facilitate a drug-lead to recognize a specific target and improve drugs efficacy. To understand this, comprehensive analysis of hydrophobic interactions, hydrogen bonding and binding affinity have been analyzed at the interface of c-Src and c-Abl kinases and 4-amino substituted 1H-pyrazolo [3, 4-d] pyrimidine compounds.Methodology
In-silico docking studies were performed, using Discovery Studio software modules LigandFit, CDOCKER and ZDOCK, to investigate the role of ligand binding affinity at the hydrophobic pocket of c-Src and c-Abl kinase. Hydrophobic and hydrogen bonding interactions of docked molecules were compared using LigPlot program. Furthermore, 3D-QSAR and MFA calculations were scrutinized to quantify the role of weak interactions in binding affinity and drug efficacy.Conclusions
The in-silico method has enabled us to reveal that a multi-targeted small molecule binds with low affinity to its respective targets. But its binding affinity can be altered by integrating the conformationally favored functional groups at the active site of the ligand-target interface. Docking studies of 4-amino-substituted molecules at the bioactive cascade of the c-Src and c-Abl have concluded that 3D structural folding at the protein-ligand groove is also a hallmark for molecular recognition of multi-targeted compounds and for predicting their biological activity. The results presented here demonstrate that hydrogen bonding and optimized hydrophobic interactions both stabilize the ligands at the target site, and help alter binding affinity and drug efficacy. 相似文献997.
Rani Pallavi Nainita Roy Rishi Kumar Nageshan Pinaki Talukdar Soundara Raghavan Pavithra Raghunath Reddy S. Venketesh Rajender Kumar Ashok Kumar Gupta Raj Kumar Singh Suresh Chandra Yadav Utpal Tatu 《The Journal of biological chemistry》2010,285(49):37964-37975
Using a pharmacological inhibitor of Hsp90 in cultured malarial parasite, we have previously implicated Plasmodium falciparum Hsp90 (PfHsp90) as a drug target against malaria. In this study, we have biochemically characterized PfHsp90 in terms of its ATPase activity and interaction with its inhibitor geldanamycin (GA) and evaluated its potential as a drug target in a preclinical mouse model of malaria. In addition, we have explored the potential of Hsp90 inhibitors as drugs for the treatment of Trypanosoma infection in animals. Our studies with full-length PfHsp90 showed it to have the highest ATPase activity of all known Hsp90s; its ATPase activity was 6 times higher than that of human Hsp90. Also, GA brought about more robust inhibition of PfHsp90 ATPase activity as compared with human Hsp90. Mass spectrometric analysis of PfHsp90 expressed in P. falciparum identified a site of acetylation that overlapped with Aha1 and p23 binding domain, suggesting its role in modulating Hsp90 multichaperone complex assembly. Indeed, treatment of P. falciparum cultures with a histone deacetylase inhibitor resulted in a partial dissociation of PfHsp90 complex. Furthermore, we found a well known, semisynthetic Hsp90 inhibitor, namely 17-(allylamino)-17-demethoxygeldanamycin, to be effective in attenuating parasite growth and prolonging survival in a mouse model of malaria. We also characterized GA binding to Hsp90 from another protozoan parasite, namely Trypanosoma evansi. We found 17-(allylamino)-17-demethoxygeldanamycin to potently inhibit T. evansi growth in a mouse model of trypanosomiasis. In all, our biochemical characterization, drug interaction, and animal studies supported Hsp90 as a drug target and its inhibitor as a potential drug against protozoan diseases. 相似文献
998.
Harmeet S. Sandhu Sameer Sapra Mukesh Gupta Kunal Nepali Raju Gautam Sunil Yadav Raj Kumar Sanjay M. Jachak Manoj Chugh Manish K. Gupta Om P. Suri K.L. Dhar 《Bioorganic & medicinal chemistry》2010,18(15):5626-5633
A series of arylidene analogues of Meldrum’s acid were synthesized and evaluated for in vitro antimalarial and antioxidant activities for the first time. The influence of various physico-chemical parameters such as dielectric constant (ε), donor number (DN), acceptor number (AN), hydrogen bond donor (HBD), hydrogen bond acceptor (HBA), and solubilizing power of the solvents on Meldrum’s acid anion generation and thus on promoting the Knoevenagel condensation of Meldrum’s acid with aryl aldehydes has been discussed. Five compounds 9l, 9m, 9n, 9r, and 9s were found to be most active against Plasmodium falciparum with IC50 values in the range of 9.68–16.11 μM. Compound 9l exhibited the most potent antimalarial activity (IC50 9.68 μM). The compounds were also found to possess antioxidant activity when tested against DPPH and ABTS free radicals. 相似文献
999.
Hypertension is a major risk factor for human morbidity and mortality through its effects on target organs like heart, brain and kidneys. More intensive treatment for the effective control of blood pressure significantly reduces the morbidity and mortality. The renin angiotensin system (RAS) is a coordinated hormonal cascade of major clinical importance in the regulation of blood pressure. The principal effector peptide of RAS is angiotensin II, which acts by binding to one of the two major angiotensin II receptors AT(1) and AT(2). Angiotensin II through AT(1) receptor mediates vast majority of biologically detrimental actions. Nonpeptidic angiotensin II (AT(1)) antagonists are the most specific means to block the renin angiotensin enzymatic cascade available presently. Majority of AT(1) antagonists are based on modifications of losartan structure, the first clinically used AT(1) antagonist. In this review, a comprehensive presentation of the literature on AT(1) receptor antagonists has been given. 相似文献
1000.
Abhinav Choubey Khyati Girdhar Aditya K. Kar Shaivya Kushwaha Manoj Kumar Yadav Debabrata Ghosh Prosenjit Mondal 《The Journal of biological chemistry》2020,295(48):16359
The incidence of diabetes, obesity, and metabolic diseases has reached an epidemic status worldwide. Insulin resistance is a common link in the development of these conditions, and hyperinsulinemia is a central hallmark of peripheral insulin resistance. However, how hyperinsulinemia leads to systemic insulin resistance is less clear. We now provide evidence that hyperinsulinemia promotes the release of soluble pro-inflammatory mediators from macrophages that lead to systemic insulin resistance. Our observations suggest that hyperinsulinemia induces sirtuin1 (SIRT1) repression and stimulates NF-κB p65 nuclear translocation and transactivation of NF-κB to promote the extracellular release of pro-inflammatory mediators. We further showed that low-dose naltrexone (LDN) abrogates hyperinsulinemia-mediated SIRT1 repression and prevents NF-κB p65 nuclear translocation. This, in turn, attenuates the hyperinsulinemia-induced release of pro-inflammatory cytokines and reinstates insulin sensitivity both in in vitro and in vivo diet-induced hyperinsulinemic mouse model. Notably, our data indicate that Sirt1 knockdown or inhibition blunts the anti-inflammatory properties of LDN in vitro. Using numerous complementary in silico and in vitro experimental approaches, we demonstrated that LDN can bind to SIRT1 and increase its deacetylase activity. Together, these data support a critical role of SIRT1 in inflammation and insulin resistance in hyperinsulinemia. LDN improves hyperinsulinemia-induced insulin resistance by reorienting macrophages toward anti-inflammation. Thus, LDN treatment may provide a novel therapeutic approach against hyperinsulinemia-associated insulin resistance. 相似文献