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There is a buzz of excitement and discussion in the protein folding and design community following the publication of papers by Stephen Mayo and colleagues, describing the implementation of their new computer-assisted strategy for protein design.
Background: Hepatocyte growth factor (HGF) is a multipotent growth factor that transduces a wide range of biological signals, including mitogenesis, motogenesis, and morphogenesis. The N-terminal (N) domain of HGF, containing a hairpin-loop region, is important for receptor binding and the potent biological activities of HGF. The N domain is also the primary binding site for heparin or heparan sulfate,...
Background: Most aminoacyl-tRNA synthetases (aaRSs) specifically recognise all or part of the anticodon triplet of nucleotides of their cognate tRNAs. Class IIa and class IIb aaRSs possess structurally distinct tRNA anticodon-binding domains. The class IIb enzymes (LysRS, AspRS and AsnRS) have an N-terminal β-barrel domain (OB-fold); the interactions of this domain with the anticodon stem-loop are...
Background: Eukaryotic initiation factor 5A (elF-5A) contains an unusual amino acid, hypusine [N ε -(4-aminobutyl-2-hydroxy)lysine]. The first step in the post-translational formation of hypusine is catalysed by the enzyme deoxyhypusine synthase (DHS). The modified version of elF-5A, and DHS, are required for eukaryotic cell proliferation. Knowledge of the three-dimensional structure of this...
Utilization of lipidic cubic phases in the crystallization of bacteriorhodopsin (bR) has yielded long sought after crystals that diffract X-rays to 2 a resolution. The resulting structure provides new information on the protein conformation and the mechanism of proton translocation. Crystallization of bR via lipidic cubic phases may be a harbinger of new membrane protein crystallization strategies.
Background: Hepatitis C virus (HCV) represents a major health concern as it is responsible for a significant number of hepatitis cases worldwide. Much research has focused on the replicative enzymes of HCV as possible targets for more effective therapeutic agents. HCV NS3 helicase may provide one such suitable target. Helicases are enzymes which can unwind double-stranded regions of DNA or RNA in...
Background: Cathepsin H is a lysosomal cysteine protease, involved in intracellular protein degradation. It is the only known mono-aminopeptidase in the papain-like family and is reported to be involved in tumor metastasis. The cathepsin H structure was determined in order to investigate the structural basis for its aminopeptidase activity and thus to provide the basis for structure-based design of...
Background: The neonatal Fc receptor (FcRn) mediates the transcytosis of maternal immunoglobulin G(IgG) across fetal and/or neonatal tissues for the acquisition of passive immunity. In adults, FcRn is involved in the maintenance of high serum IgG levels. Both processes are mediated by pH-dependent IgG binding to FcRn -FcRn binds to IgG with nanomolar affinity at pH 6, but shows no detectable binding...
Background: Hexokinase l is the pacemaker of glycolysis in brain tissue. The type l isozyme exhibits unique regulatory properties in that physiological levels of phosphate relieve potent inhibition by the product, glucose-6-phosphate (Gluc-6-P). The 100 kDa polypeptide chain of hexokinase l consists of a C-terminal (catalytic) domain and an N-terminal (regulatory) domain. Structures of ligated hexokinase...
Background: Kinesins are crucial to eukaryotic cells. They are a superfamily of motor proteins that use ATP hydrolysis to move along microtubules. Many of these motors are heterotetramers with two heavy and two light chains. The heavy chain has a globular motor domain that interacts with microtubules and shows a similar sequence throughout the family. Compared with myosin and dynein, kinesin provides...
Background: Homologous recombination is crucial for genetic diversity and repairing damaged chromosomes. In Escherichia coli cells, the RuvA, RuvB and RuvC proteins participate in the processing of an important intermediate, the Holliday junction. The RuvA-RuvB protein complex facilitates branch migration of the junction, depending on ATP hydrolysis. The atomic structure of RuvA should enable critical...
Background: The proteins of halophilic archaea require high salt concentrations both for stability and for activity, whereas they denature at low ionic strength. The structural basis for this phenomenon is not yet well understood. The crystal structure of dihydrofolate reductase (DHFR) from Haloferax volcanii (hv-DHFR) reported here provides the third example of a structure of a protein from a halophilic...
Background: Spiroplasma virus, SpV4, is a small, non-enveloped virus that infects the helical mollicute Spiroplasma melliferum. SpV4 exhibits several similarities to the Chlamydia phage, Chp1, and the Coliphages α3, φK, G4 and φX174. All of these viruses are members of the Microviridae. These viruses have isometric capsids with T = 1 icosahedral symmetry, cause lytic infections and are the only icosahedral...
Background: The interconversion of two major folate one-carbon donors occurs through the sequential activities of AND(P)-dependent methylene[H 4 ]folate dehydrogenase (D) and methenyl[H 4 ]folate cyclohydrolase (C). These activities often coexist as part of a multifunctional enzyme and there are several lines of evidence suggesting that their substrates bind at overlapping sites. Little...
Isoprenoids comprise a family of more than 23,000 natural products, among them the precursors of cholesterol and taxol. The structures of three isoprenoid-cyclizing enzymes have recently been determined and here are placed in the greater context of isoprenoid biosynthesis. On the basis of reaction mechanisms, a subdivision into class I and class II enzymes is proposed. The chain folds of these enzymes...
Replicative DNA polymerases are highly processive enzymes that polymerize thousands of nucleotides without dissociating from the DNA template. The recently determined structure of the Escherichia coli bacteriophage T7 DNA polymerase suggests a unique mechanism that underlies processivity, and this mechanism may generalize to other replicative polymerases.
Background: Calcyclin is a member of the S100 subfamily of EF-hand Ca 2+ -binding proteins. This protein has implied roles in the regulation of cell growth and division, exhibits deregulated expression in association with cell transformation, and is found in high abundance in certain breast cancer cell lines. The novel homodimeric structural motif first identified for apo calcyclin raised...
Background: Chromosome rearrangements are frequently involved in the generation of hematopoietic tumors. One type of T-cell leukemia, T-cell prolymphocytic leukemia, is consistently associated with chromosome rearrangements characterized by the juxtaposition of the TCRA locus on chromosome 14q11 and either the TCL1 gene on 14q32.1 or the MTCP1 gene on Xq28. The TCL1 gene is preferentially expressed...
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