http://hdl.handle.net/2144/1001 Tue, 21 May 2013 17:11:53 GMT 2013-05-21T17:11:53Z http://hdl.handle.net/2144/3352 The Role of Disorder in Interaction Networks: A Structural Analysis Kim, Philip M; Sboner, Andrea; Xia, Yu; Gerstein, Mark Recent studies have emphasized the value of including structural information into the topological analysis of protein networks. Here, we utilized structural information to investigate the role of intrinsic disorder in these networks. Hub proteins tend to be more disordered than other proteins (i.e. the proteome average); however, we find this only true for those with one or two binding interfaces ('single'-interface hubs). In contrast, the distribution of disordered residues in multi-interface hubs is indistinguishable from the overall proteome. Surprisingly, we find that the binding interfaces in single-interface hubs are highly structured, as is the case for multi-interface hubs. However, the binding partners of single-interface hubs tend to have a higher level of disorder than the proteome average, suggesting that their binding promiscuity is related to the disorder of their binding partners. In turn, the higher level of disorder of single-interface hubs can be partly explained by their tendency to bind to each other in a cascade. A good illustration of this trend can be found in signaling pathways and, more specifically, in kinase cascades. Finally, our findings have implications for the current controversy related to party and date-hubs. Tue, 25 Mar 2008 00:00:00 GMT http://hdl.handle.net/2144/3352 2008-03-25T00:00:00Z http://hdl.handle.net/2144/3353 Secondary Structure Effects on DNA Hybridization Kinetics: A Solution Versus Surface Comparison Gao, Yang; Wolf, Lauren K.; Georgiadis, Rosina M. The hybridization kinetics for a series of designed 25mer probe–target pairs having varying degrees of secondary structure have been measured by UV absorbance and surface plasmon resonance (SPR) spectroscopy in solution and on the surface, respectively. Kinetic rate constants derived from the resultant data decrease with increasing probe and target secondary structure similarly in both solution and surface environments. Specifically, addition of three intramolecular base pairs in the probe and target structure slow hybridization by a factor of two. For individual strands containing four or more intramolecular base pairs, hybridization cannot be described by a traditional two-state model in solution-phase nor on the surface. Surface hybridization rates are also 20- to 40-fold slower than solution-phase rates for identical sequences and conditions. These quantitative findings may have implications for the design of better biosensors, particularly those using probes with deliberate secondary structure. Wed, 05 Jul 2006 00:00:00 GMT http://hdl.handle.net/2144/3353 2006-07-05T00:00:00Z http://hdl.handle.net/2144/3351 Bromido(2,2′:6′,2′′-terpyridine)platinum(II) dibromidoaurate(I) Dimethyl Sulfoxide Solvate Kahn, Michael I.; Golen, James A.; Rheingold, Arnold L.; Doerrer, Linda H. The crystal structure of the title compound, [PtBr(C15H11N3)][AuBr2]·(CH3)2SO, exhibits infinite chains of {PtAuPt}∞ metallophilic interactions along the b axis. Two cations and one anion stack in a trimer with a unique Pt·Au distance of 3.3361 (5) Å and Pt·Pt contacts of 3.4335 (6) Å. The remaining [AuBr2]− anion forms no close contacts. Wed, 26 Aug 2009 00:00:00 GMT http://hdl.handle.net/2144/3351 2009-08-26T00:00:00Z http://hdl.handle.net/2144/3348 Antitumor Activity and Mechanism of Action of the Cyclopenta[b]benzofuran, Silvestrol Cencic, Regina; Carrier, Marilyn; Galicia-Vázquez, Gabriela; Bordeleau, Marie-Eve; Sukarieh, Rami; Bourdeau, Annie; Brem, Brigitte; Teodoro, Jose G.; Greger, Harald; Tremblay, Michel L.; Porco, John A.; Pelletier, Jerry BACKGROUND. Flavaglines are a family of natural products from the genus Aglaia that exhibit anti-cancer activity in vitro and in vivo and inhibit translation initiation. They have been shown to modulate the activity of eIF4A, the DEAD-box RNA helicase subunit of the eukaryotic initiation factor (eIF) 4F complex, a complex that stimulates ribosome recruitment during translation initiation. One flavagline, silvestrol, is capable of modulating chemosensitivity in a mechanism-based mouse model. METHODOLOGY/PRINCIPAL FINDINGS. Among a number of flavagline family members tested herein, we find that silvestrol is the more potent translation inhibitor among these. We find that silvestrol impairs the ribosome recruitment step of translation initiation by affecting the composition of the eukaryotic initiation factor (eIF) 4F complex. We show that silvestrol exhibits significant anticancer activity in human breast and prostate cancer xenograft models, and that this is associated with increased apoptosis, decreased proliferation, and inhibition of angiogenesis. We demonstrate that targeting translation by silvestrol results in preferential inhibition of weakly initiating mRNAs. CONCLUSIONS/SIGNIFICANCE. Our results indicate that silvestrol is a potent anti-cancer compound in vivo that exerts its activity by affecting survival pathways as well as angiogenesis. We propose that silvestrol mediates its effects by preferentially inhibiting translation of malignancy-related mRNAs. Silvestrol appears to be well tolerated in animals. Wed, 29 Apr 2009 00:00:00 GMT http://hdl.handle.net/2144/3348 2009-04-29T00:00:00Z