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Gavathiotis E Reyna DE Bellairs JA Leshchiner ES Walensky LD 《Nature chemical biology》2012,8(7):639-645
BCL-2 family proteins are key regulators of the apoptotic pathway. Antiapoptotic members sequester the BCL-2 homology 3 (BH3) death domains of proapoptotic members such as BAX to maintain cell survival. The antiapoptotic BH3-binding groove has been successfully targeted to reactivate apoptosis in cancer. We recently identified a geographically distinct BH3-binding groove that mediates direct BAX activation, suggesting a new strategy for inducing apoptosis by flipping BAX's 'on switch'. Here we applied computational screening to identify a BAX activator molecule that directly and selectively activates BAX. We demonstrate by NMR and biochemical analyses that the molecule engages the BAX trigger site and promotes the functional oligomerization of BAX. The molecule does not interact with the BH3-binding pocket of antiapoptotic proteins or proapoptotic BAK and induces cell death in a BAX-dependent fashion. To our knowledge, we report the first gain-of-function molecular modulator of a BCL-2 family protein and demonstrate a new paradigm for pharmacologic induction of apoptosis. 相似文献
2.
Serazev T. V. Nadezhdina E. S. Shanina N. A. Leshchiner A. D. Kalinina N. O. Morozov S. Yu. 《Molecular Biology》2003,37(6):919-925
A study was made of the in vitro interactions of virions and the coat protein (CP) of the potato virus X (PVX) with microtubules (MT). Both virions and CP cosedimented with taxol-stabilized MT. In the presence of PVX CP, tubulin polymerized to produce structures resistant to chilling. Electron microscopy revealed the aberrant character of the resulting tubulin polymers (protofilaments and their sheets), which differed from MT assembled in the presence of cell MAP2. In contrast, PVX virions induced the assembly of morphologically normal MT sensitive to chilling. Virions were shown to compete with MAP2 for MT binding, suggesting an overlap for the MT sites interacting with MAP2 and with PVX virions. It was assumed that PVX virions interact with MT in vivo and that, consequently, cytoskeleton elements participate in intracellular compartmentalization of the PVX genome. 相似文献
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Stefan C. Dentro Ignaty Leshchiner Kerstin Haase Maxime Tarabichi Jeff Wintersinger Amit G. Deshwar Kaixian Yu Yulia Rubanova Geoff Macintyre Jonas Demeulemeester Ignacio Vázquez-García Kortine Kleinheinz Dimitri G. Livitz Salem Malikic Nilgun Donmez Subhajit Sengupta Pavana Anur Clemency Jolly Peter Van Loo 《Cell》2021,184(8):2239-2254.e39
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Serazev TV Nadezhdina ES Shanina NA Leshchiner AD Kalinina NO Morozov SIu 《Molekuliarnaia biologiia》2003,37(6):1080-1088
A study was made of the in vitro interactions of virions and the coat protein (CP) of the potato virus X (PVX) with microtubules (MT). Both virions and CP cosedimented with taxol-stabilized MT. In the presence of PVX CP, tubulin polymerized to produce structures resistant to chilling. Electron microscopy revealed the aberrant character of the resulting tubulin polymers (protofilaments and their sheets), which differed from MT assembled in the presence of cell MAP2. In contrast, PVX virions induced the assembly of morphologically normal MT sensitive to chilling. Virions were shown to compete with MAP2 for MT binding, suggesting an overlap for the MT sites interacting with MAP2 and with PVX virions. It was assumed that PVX virions interact with MT in vivo and that, consequently, cytoskeleton elements participate in intracellular compartmentalization of the PVX genome. 相似文献
5.
Leshchiner AD Minina EA Rakitina DV Vishnichenko VK Solovyev AG Morozov SY Kalinina NO 《Biochemistry. Biokhimii?a》2008,73(1):50-55
A 25-kD movement protein (25K protein) encoded by the first gene of the potexvirus Potato virus X triple gene block of transport genes is essential for the viral movement in infected plants. The 25K protein belongs to superfamily 1 of NTPase/helicases and exhibits in vitro RNA helicase, Mg2+-dependent NTPase, and RNA-binding activities. In the present work, the ability of 25K protein for homologous interactions was studied using the yeast two-hybrid system, protein chemical cross-linking in the presence of glutaraldehyde, far-Western blotting, and ultracentrifugation in sucrose density gradients. The 25K protein was shown to form homodimers and homooligomers. Sites of homologous protein-protein interactions were found in both the N- and C-terminal portions of the protein. 相似文献
6.
Akinc A Zumbuehl A Goldberg M Leshchiner ES Busini V Hossain N Bacallado SA Nguyen DN Fuller J Alvarez R Borodovsky A Borland T Constien R de Fougerolles A Dorkin JR Narayanannair Jayaprakash K Jayaraman M John M Koteliansky V Manoharan M Nechev L Qin J Racie T Raitcheva D Rajeev KG Sah DW Soutschek J Toudjarska I Vornlocher HP Zimmermann TS Langer R Anderson DG 《Nature biotechnology》2008,26(5):561-569
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Green JJ Shi J Chiu E Leshchiner ES Langer R Anderson DG 《Bioconjugate chemistry》2006,17(5):1162-1169
Endothelial cells are an important cell type to both cardiovascular disease and cancer, as they play critical roles in vascular function and angiogenesis. However, effective and safe gene delivery to primary endothelial cells in the presence of serum proteins is known to be particularly challenging. A library of biodegradable poly(beta-amino esters) was synthesized for use as potential vectors. Promising vectors were optimized for high efficacy and low cytotoxicity to human umbilical vein endothelial cells (HUVECs) in serum. Vector parameters including polymer type, polymer weight, and DNA loading were varied, and biophysical properties including particle size, zeta potential, and particle stability over time were studied. While many of the poly(beta-amino ester) vectors have similar biophysical properties in the presence of buffer, their biophysical properties changed differentially in the presence of serum proteins, and the properties of these serum-interacting particles correlated to transfection efficacy. Leading poly(beta-amino ester) vectors were found to transfect HUVECs in the presence of serum significantly higher (47 +/- 9% positive, n = 10) than the best commercially available transfection reagents including jetPEI (p < 0.001) and Lipofectamine 2000 (p < 0.01). These results demonstrate the potential of a new class of biomaterials, poly(beta-amino esters), for effective human endothelial cell gene therapy. 相似文献
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Iaroslavov AA Kaplan IV Erokhina TN Morozov SIu Solov'ev AG Leshchiner AD Riakhnianskaia AA Malinin AC Stepanova LA Kiselev OI Atabekov IG 《Bioorganicheskaia khimiia》2011,37(4):496-503
Currently, a range of biologically active molecules have been attached to plant and bacterial viras nanoscaffolds, yielding stable nanoparticles that display multiple copies of the desired molecule. In this paper we propose a new method of non-covalent attachment of peptides to the surface of virios. We have demonstrated that this method is efficient in a model system that includes tobacco mosaic virus particles, synthetic polycation (quaternized poly(4-vinylpyridine) carrying ethyl ethyl pendant radicals) and polypeptide of interest. This principle of step-by-step binding to the surface of virions was used for electrostatic association with hydrophilic fragment of influenza virus haemagglutinin. 相似文献
9.
Rakitina DV Kantidze OL Leshchiner AD Solovyev AG Novikov VK Morozov SY Kalinina NO 《FEBS letters》2005,579(22):4955-4960
Coat proteins (CPs) of plant viruses are involved in different stages of the viral life cycle such as virion assembly, replication, movement, vector transmission, and regulation of host defense responses. Here, we report that the CPs of two filamentous RNA viruses, potato virus X (PVX, Potexvirus) and potato virus A (PVA, Potyvirus) exhibit an enzyme activity. The CP isolated from PVX virions possesses ATP-binding and ATPase activities. Recombinant PVX and PVA CPs produced in Escherichia coli show Mg2+-dependent ATPase and UTPase activities inhibited by antibodies against virus particles. Deletion of the C-terminal regions of these proteins diminishes their ATPase activity. 相似文献
10.
A. A. Yaroslavov I. B. Kaplan T. N. Erokhina S. Yu. Morozov A. G. Solovyev A. D. Leshchiner A. A. Rakhnyanskaya A. S. Malinin L. A. Stepanova O. I. Kiselev J. G. Atabekov 《Russian Journal of Bioorganic Chemistry》2011,37(4):441-447
A new method for noncovalent immobilization of a peptide epitope on the virion surface was developed to simplify and standardize the procedures for producing viral nanocomplexes. The efficacy of this approach was demonstrated by the example of a model system comprising the tobacco mosaic virus, synthetic cationic polymer poly-N-ethyl-4-vinylpyridinium bromide, and a model polypeptide. The principle of sequential adsorption, underlying production of the triple system virion-polycation-protein, was used for electrostatic immobilization of a recombinant hydrophilic fragment of the influenza virus hemagglutinin (Flu1-3) on the virion surface. The method provided for a significant increase in the immunogenic activity of this potential artificial vaccine protein. 相似文献
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