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Journal Issue - Volume 8 Issue 11 (1999)

Abstract Neurotrophins are a family of proteins with pleiotropic effects mediated by two distinct receptor types, namely the Trk family, and the common neurotrophin receptor p75NTR. Binding of four mammalian neurotrophins, nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF), neurotrophin‐3 (NT‐3), and neurotrophin‐4/5 (NT‐4/5), to p75NTR is studied by molecular modeling based on X‐ray structures of the neurotrophins and the...

Abstract A previous NMR investigation of model decapeptides with identical β‐strand sequences and different turn sequences demonstrated that, in these peptide systems, the turn residues played a more predominant role in defining the type of β‐hairpin adopted than cross‐strand side‐chain interactions. This result needed to be tested in longer β‐hairpin forming peptides, containing more potentially stabilizing cross‐strand hydrogen...

Abstract The folding of immunoglobulin domains requires the formation of a conserved structural disulfide. Therefore, as a general rule, they cannot be functionally expressed in the reducing environment of the cellular cytoplasm. We have previously reported that stability engineering can lead to the cytoplasmic expression of functional immunoglobulin VL domains. Here we apply rational stability engineering by consensus sequence analysis to VH...

Abstract Based on results from both equilibrium and kinetic hydrogen exchange studies of Escherichia coli ribonuclease HI (RNase H), a fragment of RNase H (eABCD) was designed. The sequence of eABCD contains less than half of the protein's primary sequence and includes the regions that were shown to be the most protected from hydrogen exchange in all previous studies of RNase H. This core fragment of RNase H encodes a well‐ordered protein with...

Abstract Excitable cells and tissues like muscle or brain show a highly fluctuating consumption of ATP, which is efficiently regenerated from a large pool of phosphocreatine by the enzyme creatine kinase (CK). The enzyme exists in tissue–as well as compartment‐specific isoforms. Numerous pathologies are related to the CK system: CK is found to be overexpressed in a wide range of solid tumors, whereas functional impairment of CK...

Abstract We report the solution structure of the chemotactic cytokine (chemokine) vMIP‐II. This protein has unique biological activities in that it blocks infection by several different human immunodeficiency virus type 1 (HIV‐1) strains. This occurs because vMIP‐II binds to a wide range of chemokine receptors, some of which are used by HIV to gain cell entry. vMIP‐II is a monomeric protein, unlike most members of the chemokine...

Abstract The factors that influence the enhanced stability observed experimentally of human rhinovirus 14 (HRV14) upon binding a hydrophobic antiviral drug have been investigated by molecular dynamics. Simulations centered about the HRV14 drug‐binding pocket allow the reliable assessment of differences in capsid protein motions of HRV14 and drug‐bound HRV14. We propose that the experimentally observed stabilization of the ligated...

Abstract The partly folded states of α‐lactalbumin (α‐LA) exposed to acid solution at pH 2.0 (A‐state) or at neutral pH upon EDTA‐mediated removal of the single protein‐bound calcium ion (apo form) have been probed by limited proteolysis experiments. These states are nowadays commonly considered to be molten globules and thus protein‐folding intermediates. Pepsin was used for proteolysis at acid pH, while proteinase K and...

Abstract The human C3a anaphylatoxin receptor (C3aR) is a G protein‐coupled receptor (GPCR) composed of seven transmem‐brane α‐helices connected by hydrophilic loops. Previous studies of chimeric C3aR/C5aR and loop deletions in C3aR demonstrated that the large extracellular loop2 plays an important role in noneffector ligand binding; however, the effector binding site for C3a has not been identified. In this study, selected charged...

Abstract We describe here a systematic investigation into the role of position a in the hydrophobic core of a model coiled‐coil protein in determining coiled‐coil stability and oligomerization state. We employed a model coiled coil that allowed the formation of an extended three‐stranded trimeric oligomerization state for some of the analogs; however, due to the presence of a Cys‐Gly‐Gly linker, unfolding occurred from the same...

Abstract β‐Lactamases are the major resistance mechanism to β‐lactam antibiotics and pose a growing threat to public health. Recently, bacteria have become resistant to β‐lactamase inhibitors, making this problem pressing. In an effort to overcome this resistance, non‐β‐lactam inhibitors of β‐lactamases were investigated for complementarity to the structure of AmpC β‐lactamase from Escherichia coli. This led to the discovery of an inhibitor,...

Abstract Endo‐β‐N‐acetylglucosaminidase H hydrolyzes the β‐(1‐4)‐glycosidic link of the N,N′‐diacetylchitobiose core of high‐mannose and hybrid asparagine‐linked oligosaccharides. Seven mutants of the active site residues, Asp130 and Glu132, have been prepared, assayed, and crystallized. They include single site mutants of each residue to the corresponding amide, to Ala and to the alternate acidic residue, and to the double amide mutant. The...

Abstract The knowledge of the binding sites of G protein‐coupled cholecystokinin receptors represents important insights that may serve to understand their activation processes and to design or optimize ligands. Our aim was to identify the amino acid of the cholecystokinin‐A receptor (CCK‐AR) binding site in an interaction with the sulfate of CCK, which is crucial for CCK binding and activity. A three‐dimensional model of the...

Abstract Lumazine synthase catalyzes the penultimate step in the synthesis of riboflavin in plants, fungi, and microorganisms. The enzyme displays two quaternary structures, the pentameric forms in yeast and fungi and the 60‐meric icosahedral capsids in plants and bacteria. To elucidate the structural features that might be responsible for differences in assembly, we have determined the crystal structures of lumazine synthase,...

Abstract Catalysis by thioredoxin reductase (TrxR) from Escherichia coli requires alternation between two domain arrangements. One of these conformations has been observed by X‐ray crystallography (Waksman G, Krishna TSR, Williams CH Jr, Kuriyan J, 1994, J Mol Biol 236:800‐816). This form of TrxR, denoted FO, permits the reaction of enzyme‐bound reduced FAD with a redox‐active disulfide on TrxR. As part of an investigation of conformational...

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