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Journal Issue - Volume 17 Issue 4 (April 2008)

Abstract Crystal structures of acetylcholinesterase complexed with ligands are compared with side‐chain conformations accessed by native acetylcholinesterase in molecular dynamics (MD) simulations. Several crystallographic conformations of a key residue in a specific binding site are accessed in a simulation of native acetylcholinesterase, although not seen in rotomer plots. Conformational changes upon ligand binding thus involve...

Abstract In the post‐genome era, there is a great need for protein‐specific affinity reagents to explore the human proteome. Antibodies are suitable as reagents, but generation of antibodies with low cross‐reactivity to other human proteins requires careful selection of antigens. Here we show the results from a proteome‐wide effort to map linear epitopes based on uniqueness relative to the entire human proteome. The analysis was...

Abstract Mercury is a ubiquitous pollutant that when absorbed is extremely toxic to a wide variety of biochemical processes. Mercury (II) is a strong, “invisible” poison that is rapidly absorbed by tissues of the intestinal tract, kidneys, and liver upon ingestion. In this study, a novel fluorescence‐based biosensor is presented that allows for the direct monitoring of the uptake and distribution of the metal under noninvasive in...

Abstract A nonredundant set of 9081 protein crystal structures in the Protein Data Bank was used to examine the solvent content, the number of polypeptide chains, and the oligomeric states of proteins in crystals as a function of crystal symmetry (as classified by crystal systems and space groups). It was found that there is a correlation between solvent content and crystal symmetry. Surprisingly, proteins crystallizing in lower...

Abstract HIV fusion is mediated by a conformational transition in which the C‐terminal region (HR2) of gp41 interacts with the N‐terminal region (HR1) to form a six‐helix bundle. Peptides derived from the HR1 form a well‐characterized, trimeric coiled‐coil bundle in the presence of HR2 peptides, but there is little structural information on the isolated HR1 trimer. Using protein design, we have designed synthetic HR1 peptides that...

Abstract A critical step in the folding pathway of globular proteins is the formation of a tightly packed hydrophobic core. Several mutational studies have addressed the question of whether tight packing interactions are present during the rate‐limiting step of folding. In some of these investigations, substituted side chains have been assumed to form native‐like interactions in the transition state when the folding rates of mutant...

Abstract Although 8‐anilinonaphthalene‐1‐sulfonic acid (ANS) is frequently used in protein folding studies, the structural and thermodynamic effects of its binding to proteins are not well understood. Using high‐resolution two‐dimensional NMR and human interleukin‐1 receptor antagonist (IL‐1ra) as a model protein, we obtained detailed information on ANS–protein interactions in the absence and presence of urea. The effects of ambient...

Abstract The human tissue kallikrein (KLK) family contains 15 secreted serine proteases that are expressed in a wide range of tissues and have been implicated in different physiological functions and disease states. Of these, KLK1 has been shown to be involved in the regulation of multiple physiological processes such as blood pressure, smooth muscle contraction, and vascular cell growth. KLK6 is overexpressed in breast and ovarian...

Abstract Membrane proteins play a fundamental role in human disease and therapy, but suffer from a lack of structural and functional information compared to their soluble counterparts. The paucity of membrane protein structures is primarily due to the unparalleled difficulties in obtaining detergent‐solubilized membrane proteins at sufficient levels and quality. We have developed an in vitro evolution strategy for optimizing the...

Abstract The crystal structure of Escherichia coli ribonuclease I (EcRNase I) reveals an RNase T2‐type fold consisting of a conserved core of six β‐strands and three α‐helices. The overall architecture of the catalytic residues is very similar to the plant and fungal RNase T2 family members, but the perimeter surrounding the active site is characterized by structural elements specific for E. coli. In the structure of EcRNase I in complex with a...

Abstract Enoyl–acyl carrier protein (ACP) reductases are critical for bacterial type II fatty acid biosynthesis and thus are attractive targets for developing novel antibiotics. We determined the crystal structure of enoyl–ACP reductase (FabK) from Streptococcus pneumoniae at 1.7 Å resolution. There was one dimer per asymmetric unit. Each subunit formed a triose phosphate isomerase (TIM) barrel structure, and flavin mononucleotide (FMN) was...

Abstract The peroxiredoxins (PRDXs) define a superfamily of thiol‐dependent peroxidases able to reduce hydrogen peroxide, alkyl hydroperoxides, and peroxynitrite. Besides their cytoprotective antioxidant function, PRDXs have been implicated in redox signaling and chaperone activity, the latter depending on the formation of decameric high‐molecular‐weight structures. PRDXs have been mechanistically divided into three major...

Abstract Progranulin is a secreted protein with important functions in several physiological and pathological processes, such as embryonic development, host defense, and wound repair. Autosomal dominant mutations in the progranulin gene cause frontotemporal dementia, while overexpression of progranulin promotes the invasive progression of a range of tumors, including those of the breast and the brain. Structurally, progranulin...

Abstract Renilla luciferase (RLUC) is a versatile tool for gene expression assays and in vivo biosensor applications, but its catalytic mechanism remains to be elucidated. RLUC is evolutionarily related to the α/β hydrolase family. Its closest known homologs are bacterial dehalogenases, raising the question of how a protein with a hydrolase fold can function as a decarboxylating oxygenase. Molecular docking simulations with the...

Abstract Expressed protein ligation (EPL) is an intein‐based approach that has been used for protein engineering and biophysical studies of protein structures. One major problem of the EPL is the low yield of final ligation product, primarily due to the complex procedure of the EPL, preventing EPL from gaining popularity in the research community. Here we report an efficient on‐column EPL strategy, which focuses on enhancing the...

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