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Journal Issue - Volume 14 Issue 7 (July 2005)

Abstract Heat shock protein 40s (Hsp40s) and heat shock protein 70s (Hsp70s) form chaperone partnerships that are key components of cellular chaperone networks involved in facilitating the correct folding of a broad range of client proteins. While the Hsp40 family of proteins is highly diverse with multiple forms occurring in any particular cell or compartment, all its members are characterized by a J domain that directs their...

Abstract The unfolding process of the blue copper protein rusticyanin (Rc) as well as its dynamic and D2O/H2O exchange properties in an incipient unfolded state have been studied by heteronuclear NMR spectroscopy. Titrations of apo, Cu(I), and Cu(II)Rc with guanidinium chloride (GdmCl) show that the copper ion stabilizes the folded species and remains bound in the completely unfolded state. The oxidized state of the copper ion is more efficient...

Abstract Topology predictions for integral membrane proteins can be substantially improved if parts of the protein can be constrained to a given in/out location relative to the membrane using experimental data or other information. Here, we have identified a set of 367 domains in the SMART database that, when found in soluble proteins, have compartment‐specific localization of a kind relevant for membrane protein topology...

Abstract Eukaryotic membrane proteins cannot be produced in a reliable manner for structural analysis. Consequently, researchers still rely on trial‐and‐error approaches, which most often yield insufficient amounts. This means that membrane protein production is recognized by biologists as the primary bottleneck in contemporary structural genomics programs. Here, we describe a study to examine the reasons for successes and failures...

Abstract We investigate all‐atom potentials of mean force for estimating free energies in protein folding and fold recognition. We search through the space potentials and design novel atomic potentials with a random mixing approximation and a contact‐correlated Gaussian approximation of decoy states. We show that the two derived potentials are highly correlated, supporting the use of the random energy model as an accurate...

Abstract We report here a recombinant expression system that allows production of large quantities of Alzheimer's Aβ(1–40) peptide. The material is competent to dissolve in water solutions with “random‐coil properties,” although its conformation and factual oligomerization state are determined by the physico‐chemical solution conditions. When dissolved in 50 mM sodium phosphate buffer (pH 7.4) at 37°C, the peptide is able to undergo...

Abstract Acyl ureas were discovered as a novel class of inhibitors for glycogen phosphorylase, a molecular target to control hyperglycemia in type 2 diabetics. This series is exemplified by 6‐{2,6‐Dichloro‐ 4‐[3‐(2‐chloro‐benzoyl)‐ureido]‐phenoxy}‐hexanoic acid, which inhibits human liver glycogen phosphorylase a with an IC50 of 2.0 μM. Here we analyze four crystal structures of acyl urea derivatives in complex with rabbit muscle glycogen...

Abstract We extended a mean‐field model to proteins with all atomic detail. The all‐atom mean‐field model was used to calculate the dynamic and thermodynamic properties of a three‐helix bundle fragment of Staphylococcal protein A (Protein Data Bank [PDB] ID 1BDD) and α‐spectrin SH3 domain protein (PDB ID 1SHG). We show that a model with all‐atomic detail provides a significantly more accurate prediction of flexibility of residues in proteins...

Abstract Receptor–ligand interactions between synthetic peptides and normal human erythrocytes were studied to determine Plasmodium falciparum merozoite surface protein‐3 (MSP‐3) FC27 strain regions that specifically bind to membrane surface receptors on human erythrocytes. Three MSP‐3 protein high activity binding peptides (HABPs) were identified; their binding to erythrocytes became saturable, had nanomolar affinity constants, and became...

Abstract The kinetics of proton transfer in Green Fluorescent Protein (GFP) have been studied as a model system for characterizing the correlation between dynamics and function of proteins in general. The kinetics in EGFP (a variant of GFP) were monitored by using a laser‐induced pH jump method. The pH was jumped from 8 to 5 by nanosecond flash photolysis of the “caged proton,” o‐nitrobenzaldehyde, and subsequent proton transfer was...

Abstract There are more than 200 completed genomes and over 1 million nonredundant sequences in public repositories. Although the structural data are more sparse (∼13,000 nonredundant structures solved to date), several powerful sequence‐based methodologies now allow these structures to be mapped onto related regions in a significant proportion of genome sequences. We review a number of publicly available strategies for providing...

Abstract Serum Amyloid A (SAA) is an acute phase reactant protein that is predominantly found bound to high‐density lipoprotein in plasma. Upon inflammation, the plasma concentration of SAA can increase dramatically, occasionally leading to the development of amyloid A (AA) amyloidosis, which involves the deposition of SAA amyloid fibrils in major organs. We previously found that the murine isoform SAA2.2 exists in aqueous solution...

Abstract A recurring obstacle for structural genomics is the expression of insoluble, aggregated proteins. In these cases, the use of alternative salvage strategies, like in vitro refolding, is hindered by the lack of a universal refolding method. To overcome this obstacle, fractional factorial screens have been introduced as a systematic and rapid method to identify refolding conditions. However, methodical analyses of the...

Abstract Eukaryotic cells have evolved DNA damage checkpoints in response to genome damage. They delay the cell cycle and activate repair mechanisms. The kinases at the heart of these pathways and the accessory proteins, which localize to DNA lesions and regulate kinase activation, are conserved from yeast to mammals. For Saccharomyces cerevisiae Rad9, a key adaptor protein in DNA damage checkpoint pathways, no clear human ortholog has yet been...

Abstract Methylenetetratetrahydromethanopterin reductase (Mer) is involved in CO2 reduction to methane in methanogenic archaea and catalyses the reversible reduction of methylenetetrahydromethanopterin (methylene‐H4MPT) to methyl‐H4MPT with coenzyme F420H2, which is a reduced 5′‐deazaflavin. Mer was recently established as a TIM barrel structure containing a nonprolyl cis‐peptide bond but the binding site of the substrates remained elusive. We report here on the...

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