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951.
Internal Dynamics of Dynactin CAP-Gly Is Regulated by Microtubules and Plus End Tracking Protein EB1
Si Yan Huilan Zhang Guangjin Hou Shubbir Ahmed John C. Williams Tatyana Polenova 《The Journal of biological chemistry》2015,290(3):1607-1622
CAP-Gly domain of dynactin, a microtubule-associated activator of dynein motor, participates in multiple cellular processes, and its point mutations are associated with neurodegenerative diseases. Recently, we have demonstrated that conformational plasticity is an intrinsic property of CAP-Gly. To understand its origin, we addressed internal dynamics of CAP-Gly assembled on polymeric microtubules, bound to end-binding protein EB1 and free, by magic angle spinning NMR and molecular dynamics simulations. The analysis of residue-specific dynamics of CAP-Gly on time scales spanning nano- through milliseconds reveals its unusually high mobility, both free and assembled on polymeric microtubules. On the contrary, CAP-Gly bound to EB1 is significantly more rigid. Molecular dynamics simulations indicate that these motions are strongly temperature-dependent, and loop regions are surprisingly mobile. These findings establish the connection between conformational plasticity and internal dynamics in CAP-Gly, which is essential for the biological functions of CAP-Gly and its ability to bind to polymeric microtubules and multiple binding partners. In this work, we establish an approach, for the first time, to probe atomic resolution dynamic profiles of a microtubule-associated protein assembled on polymeric microtubules. More broadly, the methodology established here can be applied for atomic resolution analysis of dynamics in other microtubule-associated protein assemblies, including but not limited to dynactin, dynein, and kinesin motors assembled on microtubules. 相似文献
952.
Chao Xu ) Ke Liu Hazem Ahmed Peter Loppnau Matthieu Schapira Jinrong Min 《The Journal of biological chemistry》2015,290(41):24902-24913
N6-Methyladenosine (m6A) is the most abundant internal modification in RNA and is specifically recognized by YT521-B homology (YTH) domain-containing proteins. Recently we reported that YTHDC1 prefers guanosine and disfavors adenosine at the position preceding the m6A nucleotide in RNA and preferentially binds to the GG(m6A)C sequence. Now we systematically characterized the binding affinities of the YTH domains of three other human proteins and yeast YTH domain protein Pho92 and determined the crystal structures of the YTH domains of human YTHDF1 and yeast Pho92 in complex with a 5-mer m6A RNA, respectively. Our binding and structural data revealed that the YTH domain used a conserved aromatic cage to recognize m6A. Nevertheless, none of these YTH domains, except YTHDC1, display sequence selectivity at the position preceding the m6A modification. Structural comparison of these different YTH domains revealed that among those, only YTHDC1 harbors a distinctly selective binding pocket for the nucleotide preceding the m6A nucleotide. 相似文献
953.
Raju Dash Mir Muhammad Nasir Uddin S.M. Zahid Hosen Zahed Bin Rahim Abu Mansur Dinar Mohammad Shah Hafez Kabir Ramiz Ahmed Sultan Ashekul Islam Md Kamrul Hossain 《Bioinformation》2015,11(12):543-549
Cyclooxygenase-2 (COX-2) catalyzed synthesis of prostaglandin E2 and it associates with tumor growth, infiltration, and metastasis
in preclinical experiments. Known inhibitors against COX-2 exhibit toxicity. Therefore, it is of interest to screen natural compounds
like flavanoids against COX-2. Molecular docking using 12 known flavanoids against COX-2 by FlexX and of ArgusLab were
performed. All compounds showed a favourable binding energy of >-10 KJ/mol in FlexX and > -8 kcal/mol in ArgusLab.
However, this data requires in vitro and in vivo verification for further consideration. 相似文献
954.
Md. Kawser Ahmed Md. Habibullah-Al-Mamun Md. Monirul Islam Mosammat Salma Akter Mohammad Shahneawz Khan 《人类与生态风险评估》2015,21(1):146-156
Arsenic is an environmental contaminant and potential carcinogen. Toxicological assessment of As, which causes hematological alterations and chromosomal aberrations, was studied in freshwater fish Oreochromis mossambicus. Fish were exposed to 3 ppm, 28 ppm, and 56 ppm concentrations of sodium arsenite (NaAsO2) and blood samples were collected after 48 h, 96 h, and 192 h of exposure. Hematological assay of exposed fish revealed abnormal mature and immature erythrocytes, deformed erythrocytes (spindle-shaped and triangular erythrocytes) and erythrocytes with segmented nuclei in all treatments. Arsenic exposure induced chromosomal aberration in a concentration-dependent manner, whereas, a decreasing trend was found after 192 h exposure. Observations on blood cells of exposed fish revealed chromosome breaks, chromatid breaks, and chromatid gaps. The alterations and aberrations of these parameters can be effectively used to assess toxicological effects of As on fish in the aquatic environment and at the same time this study elucidates the potential risks to humans who live in arsenic-contaminated areas. 相似文献
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Beres C de Nazaré FV de Souza NC Miguel MA Werneck MM 《Biosensors & bioelectronics》2011,30(1):328-332
Cells detection is crucial in microbiological analysis of clinical, food, water or environmental samples. However, currently employed methods are time consuming. Plastic optical fiber (POF) biosensors consist in a viable alternative for rapid and inexpensive scheme for detection. In order to study the sensitivity of tapers for microbiological detection, geometric parameters are studied, such as the taper waist diameter since the formation of taper regions are the key sensing element in this particular type of sensors. In this study, a series of POF taper sensors were prepared using a specially developed tapering machine, and the dispersion of geometric dimensions is evaluated, aiming to achieve the best tapering characteristics which will provide a better sensitivity on the sensor response. The fiber tapers that presented the finest results were those constructed in U-shaped (bended) configurations, with taper waist diameters ranging from 0.40 mm up to 0.50 mm. These fiber tapers were used as the main section of the monitoring device, and when chemically treated as immunosensors for the detection of bacteria, yeast and erythrocytes. 相似文献
959.
A series of new 4β-carbamoyl epipodophyllotoxin analogues have been synthesized and evaluated for their anticancer activity against eleven cancer cell lines including Zr-75-1, MCF7, KB, Gurav, DWD, Colo 205, A-549, Hop62, PC3, SiHa and A-2780. Most of the compounds exhibited better growth-inhibition activities against tested cell lines than that of etoposide. Further, compounds 6g and 6i are also evaluated for their DNA topoisomerase-II (topo-II) inhibition activity and they exhibited significant inhibition of topo-II catalytic activity comparable to etoposide. 相似文献
960.
The bioavailability of therapeutic agents from eye drops is usually limited due to corneal barrier functions and effective
eye protective mechanisms. Therefore, the current study aims to enhance ocular bioavailability of brimonidine, a potent antiglaucoma
drug, through the preparation of ocular inserts. Solvent casting technique was employed to prepare the inserts using polyvinylpyrrolidone
K-90 (PVP K-90) as film-forming polymer blended with different viscosity grades of bioadhesive polymers namely hydroxypropyl
methycellulose, carbopol, sodium alginate, and chitosan. The prepared ocular inserts were evaluated for various physicochemical
parameters, swelling behavior, and in vitro release patterns. Sodium alginate-based ocular inserts revealed the most sustainment in drug release (99% at 6 h), so it
was selected for further modifications via coating it, on one side or dual sides, using hydrophobic film composed of either
ethylcellulose or Eudragit RSPO. The obtained in vitro release results for the modified ocular inserts revealed that ethylcellulose is superior to Eudragit RSPO in terms of brimonidine
release sustainment effect. Ocular inserts composed of 7% PVP K-90, 1.5% low molecular weight sodium alginate with or without
ethylcellulose coat were able to sustain the in vitro release of brimonidine. Their therapeutic efficacy regarding intraocular pressure (IOP) lowering effect when inserted in
albino rabbits eyes showed superior sustainment effect compared with that of brimonidine solution. Furthermore, due to both
the mucoadhesive property and the drug sustainment effect, the one-side-coated ocular insert showed more IOP lowering effect
compared with that of its non-coated or dual-side-coated counterpart. 相似文献