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Background: The Src family of tyrosine kinases is involved in the propagation of intracellular signals from many transmembrane receptors. Each member of the family contains two domains that regulate interactions with other molecules, one of which is the Src homology 3 (SH3) domain. Although structures have previously been determined for SH3 domains, and ideas about peptide-binding modes have been...
Background Glucose homeostasis is maintained by the processes of glycolysis and gluconeogenesis. The importance of these pathways is demonstrated by the severe and life threatening effects observed in various forms of diabetes. The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase catalyzes both the synthesis and degradation of fructose-2,6-bisphosphate, a potent regulator of...
Background The human α-interferon (huIFN-α) family displays broad spectrum antiviral, antiproliferative and immunomodulatory activities on a variety of cell types. The diverse biological activities of the IFN-α's are conveyed to cells through specific interactions with cell-surface receptors. Despite considerable effort, no crystal structure of a member of this family has yet been reported, because...
Background: Research on high-alkaline proteases, such as serine protease PB92, has been largely inspired by their industrial application as protein-degrading components of washing powders. Serine protease PB92 is a member of the subtilase family of enzymes, which has been extensively studied. These studies have included exhaustive protein engineering investigations and X-ray crystallography, in order...
Background: Bluetongue virus (BTV), which belongs to the Reoviridae family and orbivirus genus, is a non-enveloped, icosahedral, double-stranded RNA virus. Several protein layers enclose its genome; upon cell entry the outer layer is stripped away leaving a core, the surface of which is composed of VP7. The structure of the trimeric VP7 molecule has previously been determined using X-ray crystallography...
Background: DNA helicases play a fundamental role in all aspects of nucleic acid metabolism and defects in these enzymes have been implicated in a number of inherited human disorders. DnaB is the major replicative DNA helicase in Escherichia coli and has been used as a model system for studying the structure and function of hexameric helicases. The native protein is a hexamer of identical subunits,...
Background: Myotrophin is a 12.5 kDa protein that appears to have a key role in the initiation of cardiac hypertrophy, a central process in many heart diseases. Myotrophin primarily comprises ankyrin-like (ANK) repeats, the 33 amino acid motifs involved in a wide range of protein-protein interactions. As a first step in the structure-based search for cardiac hypertrophy antagonists and in order to...
Background: The redox proteins that incorporate a thioredoxin fold have diverse properties and functions. The bacterial protein-folding factor DsbA is the most oxidizing of the thioredoxin family. DsbA catalyzes disulfide-bond formation during the folding of secreted proteins. The extremely oxidizing nature of DsbA has been proposed to result from either domain motion or stabilizing active-site interactions...
Background: Glutamate mutase is an adenosylcobamide (coenzyme B 12 ) dependent enzyme that catalyzes the reversible rearrangement of (2S)-glutamate to (2S,3S)-3-methylaspartate. The enzyme from Clostridium tetanomorphum comprises two subunits (of 53.7 and 14.8 kDa) and in its active form appears to be an α 2 β 2 tetramer. The smaller subunit, termed MutS, has been characterized...
Background: Inactive heterotrimeric G proteins are composed of a GDP-bound α subunit (G α ) and a stable heterodimer of G β and G γ subunits. Upon stimulation by a receptor, G α subunits exchange GDP for GTP and dissociate from G βγ , both G α and G βγ then interact with downstream effectors. Isoforms of G α , G β and...
Background: Conventional isoforms (α, β and γ) of protein kinase C (PKC) are synergistically activated by phosphatidylserine and Ca 2+ ; both bind to C2 domains located within the PKC amino-terminal regulatory regions. C2 domains contain a bipartite or tripartite Ca 2+ -binding site formed by opposing loops at one end of the protein. Neither the structural basis for cooperativity...
Background: DNA ligases catalyse phosphodiester bond formation between adjacent bases in nicked DNA, thereby sealing the nick. A key step in the catalytic mechanism is the formation of an adenylated DNA intermediate. The adenyl group is derived from either ATP (in eucaryotes and archaea) or NAD + 4 (in bacteria). This difference in cofactor specificity suggests that DNA ligase may be a useful...
Background: Infection of male Escherichia coli cells by filamentous Ff bacteriophages (M13, fd, and f1) involves interaction of the phage minor coat gene 3 protein (g3p) with the bacterial F pilus (primary receptor), and subsequently with the integral membrane protein TolA (coreceptor). G3p consists of three domains (N1, N2, and CT). The N2 domain interacts with the F pilus, whereas the N1 domain...
Background: Mammalian purple acid phosphatases are highly conserved binuclear metal-containing enzymes produced by osteoclasts, the cells that resorb bone. The enzyme is a target for drug design because there is strong evidence that it is involved in bone resorption.Results: The 1.55A resolution structure of pig purple acid phosphatase has been solved by multiple isomorphous replacement. The enzyme...
Background: DNA primases catalyse the synthesis of the short RNA primers that are required for DNA replication by DNA polymerases. Primases comprise three functional domains: a zinc-binding domain that is responsible for template recognition, a polymerase domain, and a domain that interacts with the replicative helicase, DnaB.Results: We present the crystal structure of the zinc-binding domain of...
Background: Proteins from thermophilic organisms usually show high intrinsic thermal stability but have structures that are very similar to their mesophilic homologues. From prevous studies it is difficult to draw general conclusions about the structural features underlying the increased thermal stability of thermophilic proteins.Results: In order to reveal the general evolutionary strategy for changing...
Background: Lesions in the gene for frataxin, a nuclear-encoded mitochondrial protein, cause the recessively inherited condition Friedreich's ataxia. It is thought that the condition arises from disregulation of mitochondrial iron homeostasis, with concomitant oxidative damage leading to neuronal death. Very little is, as yet, known about the biochemical function of frataxin.Results: Here, we show...
Background: The traditional picture of charged amino acids in globular proteins is that they are almost exclusively on the outside exposed to the solvent. Buried charges, when they do occur, are assumed to play an essential role in catalysis and ligand binding, or in stabilizing structure as, for instance, helix caps.Results: By analyzing the amount and distribution of buried charged surface and charges...
Ap 4 A hydrolases are Nudix enzymes that regulate intracellular dinucleoside polyphosphate concentrations, implicating them in a range of biological events, including heat shock and metabolic stress. We have demonstrated that ATP.MgF x can be used to mimic substrates in the binding site of Ap 4 A hydrolase from Lupinus angustifolius and that, unlike previous substrate analogs,...
Growth of high-quality crystals is a major obstacle in many structural investigations. In recent years, the techniques for screening crystals have improved dramatically, whereas the methods for obtaining large crystals have progressed more slowly. This is an important issue since, although many structures can be solved from small crystals with synchrotron radiation, it is far easier to solve and refine...
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