Protein disrupters

Liu Y, Jones M, Hingtgen CM, Bu G, Laribee N, Tanzi RE, Moir RD, Nath A, He JJ (2000) Uptake of HIV-1 tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands. Nat Med 6 1380-1387... 

C. difficile history of antibiotic use, advanced age, underlying illness 5-10 days of antibacteria treatment (range 1st day to 10 weeks of antibiotics) mild to severe inflammatory diarrhea toxins A and B monoglucosylation of Rho protein - disruption of actin cytoskeleton —> mucosal disruption. - COX-2 - prostaglandin E2 —> synthesis of inflammatory cytokines... 

Prohne is a secondary amine whose presence in a protein disrupts normal secondary structure. 

This chapter will focus on a unique problem encountered during recovery of intracellulary produced proteins. Disruption of cells produces a mixture of nucleic acids and proteins in the solution from which the desired proteins must be fractionated. Typical separation schemes involve first the removal of nucleic acids from solution by precipitation. The desired protein is then isolated and purified from the mixture of remaining nucleic acids and proteins. A scheme for recovery of intracellular bacterial enzyme tartrate dehydrogenase from cell paste is shown in Fig. 1. Material balance at the different stages of the scheme in two different experiments showed that 53-60% loss in enzyme activity took place during precipitation of nucleic acids by protamine sulfate and during ammonium sulfate fractionation of proteins (Table 2). Reduction in volume, removal of major nonprotein... 

Schmitz, 1., and Rao, A. L. N. (1998). Deletions in the conserved amino-terminal basic arm of cucumber mosaic virus coat protein disrupt virion assembly but-do not abolish infectivity and cell-to-cell movement. Virology 248, 323-331. 

The Smac protein promotes apoptosis by neutralizing the lAP proteins through interactions of the Smac N-terminal region with the BIR domains of the lAP (31, 32). The interaction between Smac and lAP proteins disrupts the LAP inhibition of caspases, which allows caspase activation and eventual cell suicide. In vivo and in vitro studies reveal that cell kiUing via either the intrinsic or the extrinsic pathways can be enhanced by Smac mimetics (33-36). Collectively, these results suggest that Smac mimetics that bind to the BIR domains of the lAPs extricate the caspases in a manner analogous to Smac. 

Organic solvents such as ethyl alcohol and acetone are capable of forming intermolecular hydrogen bonds with protein disrupting the intramolecular hydrogen bonding. This causes precipitation of protein. 

Acidic and basic reagents cause changes in pH, which alter the charges present on the side chain of protein disrupting the salt linkages. 

Yamin G (2009) NMDA receptor-dependent signaling pathways that underlie amyloid beta-protein disruption of LTP in the hippocampus. J Neurosci Res 87(8) 1729-1736... 

Rational inhibitor design offers a compelling alternative for the identification of protein-protein disrupters as it is based on a structural knowledge of the interface. In particular, synthetic scaffolds that mimic the key elements of a protein surface can potentially lead to small molecules with the full activity of a protein domain, a fraction of the molecular weight, and no peptide bonds. Furthermore, lead compounds derived from rational design can be readily optimized by structure-activity relationship (SAR) studies. 

Protein-protein disruption by multivalent scaffolded binding is a method used to pursue a potential HIV-1 therapy. The proteomimetic calix[4]arene 6 prevents fusion and entry of the HIV-1 virus by antibody mimicry. It disrupts protein-protein interaction between the cell membrane s CD4 cell receptor and gpl20 viral envelope. The cone conformation was fixed with alkyl groups and the upper rim was fashioned with aromatic diacids to create 6. It is proposed that 6 interacts with gpl20 by electrostatic interactions from the diacids and positively charged residues, and hydrophobic interactions with the calixarene s core [25, 26] (Fig. 23.11). 

With some enzymes, the cleavage of one or more internal peptide bonds does not cause protein disruption and can in fact lead to an increase in enzyme activity. This occurs not only during the processing of proenzymes, such as the conversion of trypsinogen to trypsin or chy-motrypsinogen to chymotrypsin, but also with intracellular enzymes such as hepatic fructose bisphosphatase (Pontremoli et al., 1973). This enzyme does not fall apart upon limited proteolytic cleavage, because... 

Gunning and co-workers have reported a novel family of hybrid peptidomimetic STAT3 inhibitors (417) of lead inhibitor compound (R = 4 -C0NH2) bound to STAT3 protein, disrupted phosphopeptide-STAT3... 

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