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PubMed2005

Sequence to Structure (S2S): display, manipulate and interconnect RNA data from sequence to structure.

SUMMARY: Efficient RNA sequence manipulations (such as multiple alignments) need to be constrained by rules of RNA structure folding. The structural knowledge has increased dramatically in the last years with the accumulation of several large RNA structures similar to those of the bacterial ribosome subunits. However, no tool in the RNA community provides an easy way to link and integrate progress made at the sequence level using the available three-dimensional information. Sequence to Structure (S2S) proposes a framework in which an user can easily display, manipulate and interconnect heterogeneous RNA data, such as multiple sequence alignments, secondary and tertiary structures. S2S has been implemented using the Java language and has been developed and tested under UNIX systems, such as Linux and MacOSX. AVAILABILITY: S2S is available at http://bioinformatics.org/S2S/.

Algorithms↗
PubMed2003

Crystal structure of chloroplastic ascorbate peroxidase from tobacco plants and structural insights into its instability.

Ascorbate peroxidase (APX) is a heme-containing protein that plays a central role in scavenging H(2)O(2) in higher plants. The structure of stromal APX (sAPX) was determined at 1.6 A to an R-factor of 19.1% and an R-free-factor of 22.3%. The electrostatic potential of the gamma-channel that connects the molecular surface of sAPX to the gamma-edge of heme was more positive than that of cytosolic APX (cAPX) from pea, so sAPX might bind more easily with ascorbate than cAPX. The overall structure of sAPX was similar to those of cAPX from pea and cytochrome c peroxidase (CCP) from yeast, with a substantial difference in a loop structure located in the vicinity of the heme. The side chain of Arg169 in sAPX corresponding to His169 in cAPX and His181 in CCP extended in the opposite direction from the heme, forming two hydrogen bonds with carbonyl groups in the loop structure. The rapid inactivation of sAPX might be due to the characteristic conformation of Arg169 owing to the loop structure of sAPX.

Ascorbate Peroxidases↗
PubMed2006

Comparative structural biology of the genome: nano-scale imaging of single nucleus from different kingdoms reveals the common physicochemical property of chromatin with a 40 nm structural unit.

Genome function is closely linked to the higher-order chromatin structures. To reveal a structural basis for the interphase chromatin organization, the 'on-substrate' lysis procedure was applied to nuclei isolated from human HeLa cells, chicken erythrocyte cells and yeast Schizosaccharomyces pombe, which possessed different intrinsic properties of the genomes such as histone composition and inter-nucleosomal distance. The isolated nuclei on a coverslip were successively treated with a detergent and a high-salt solution to extract the nuclear membrane and the nucleoplasm, and therefore, atomic force microscopy (AFM) visualized the structural changes in response to the lysis procedure. After the nucleoplasm was extracted, AFM clarified that chromatin fibers, approximately 40 nm in width, were partially released out of the nuclei and that the other chromatin still remaining in the nuclei was composed of granular structures with diameter of 80-100 nm. Thus, these results suggest that the approximately 40 nm fiber would be a stable structural unit and fold the 80-100 nm granules into a one-step higher unit. A common mechanism could be implied regardless of the intrinsic properties of the eukaryotic genomes.

Animals↗
PubMed1999

Structural motif of phosphate-binding site common to various protein superfamilies: all-against-all structural comparison of protein-mononucleotide complexes.

In order to search for a common structural motif in the phosphate-binding sites of protein-mononucleotide complexes, we investigated the structural variety of phosphate-binding schemes by an all-against-all comparison of 491 binding sites found in the Protein Data Bank. We found four frequently occurring structural motifs composed of protein atoms interacting with phosphate groups, each of which appears in different protein superfamilies with different folds. The most frequently occurring motif, which we call the structural P-loop, is shared by 13 superfamilies and is characterized by a four-residue fragment, GXXX, interacting with a phosphate group through the backbone atoms. Various sequence motifs, including Walker's A motif or the P-loop, turn out to be a structural P-loop found in a few specific superfamilies. The other three motifs are found in pairs of superfamilies: protein kinase and glutathione synthetase ATPase domain like, actin-like ATPase domain and nucleotidyltransferase, and FMN-linked oxidoreductase and PRTase.

Actins↗
PubMed1999

Secondary structures without backbone: an analysis of backbone mimicry by polar side chains in protein structures.

Backbone mimicry by the formation of closed-loop C7, C10 and C13 (mimics of gamma-, beta- and alpha-turns) conformations through side chain-main chain hydrogen bonds by polar groups is a frequent observation in protein structures. A data set of 250 non-homologous and high-resolution protein crystal structures was used to analyze these conformations for their characteristic features. Seven out of the nine polar residues (Ser, Thr, Asn, Asp, Gln, Glu and His) have hydrogen bonding groups in their side chains which can participate in such mimicry and as many as 15% of all these polar residues engage in such conformations. The distributions of dihedral angles of these mimics indicate that only certain combinations of the dihedral angles involved aid the formation of these mimics. The observed examples were categorized into various classes based on these combinations, resulting in well defined motifs. Asn and Asp residues show a very high capability to perform such backbone secondary structural mimicry. The most highly mimicked backbone structure is of the C10 conformation by the Asx residues. The mimics formed by His, Ser, Thr and Glx residues are also discussed. The role of such conformations in initiating the formation of regular secondary structures during the course of protein folding seems significant.

Databases, Factual↗
PubMed1995

Accurate prediction of protein secondary structural class with fuzzy structural vectors.

The prerequisites for accurate prediction of protein secondary structural class (all-alpha, all-beta, alpha+beta, alpha/beta or multidomain) were studied, and a new similarity-based method is presented for the prediction of the secondary structural class of a protein from its sequence. The new method uses representatives of nuclear families as a learning set. For the sequence to be predicted, the method produces a vector of certainty factors called a fuzzy structural vector. Validation with independent test sets shows that the prediction accuracy of the proposed method has clear dependency on the representativity of the learning set. The representatives obtained from the nuclear families of the Brookhaven Protein Data Bank (PDB) were shown to give accurate predictions for PDB proteins, whilst the amino acid composition-based methods used previously achieve their maximum predictability with relatively limited learning sets, and they remain inaccurate even with highly representative learning sets. The usability of the new method is increased further by the fuzzy structural vectors, which substantially reduce the risk of misclassification and realistically describe vague secondary structural tendencies.

Algorithms↗
PubMed2003

Hepatitis C virus IRES efficiency is unaffected by the genomic RNA 3'NTR even in the presence of viral structural or non-structural proteins.

Hepatitis C virus (HCV) translation is mediated by an IRES structure. Instead of a poly(A) tail, the 3' end of the genome contains a tripartite 3'NTR composed of a non-conserved region, a polypyrimidine tract and a highly conserved stretch of 98 nt, termed the 3'X region. Using a set of bicistronic recombinant DNA constructs expressing two reporter genes separated by the HCV IRES, it was determined whether the HCV 3'NTR sequence, in the presence or absence of HCV proteins, played a role in the efficiency of HCV IRES-dependent translation ex vivo. Bicistronic expression cassettes were transfected into hepatic and non-hepatic cell lines. These results show that neither the entire 3'NTR nor the 3'X sequence alters IRES-dependent translation efficiency, whatever the cell line tested. A potential effect of the 3'NTR on IRES-dependent translation in the presence of HCV proteins was investigated further. Neither non-structural nor structural HCV proteins had any effect on the efficiency of IRES in this system. In addition, in order to mimic HCV genome organization, monocistronic expression cassettes containing the IRES and a Core-DsRed fusion gene were constructed with or without the 3'NTR. In this context, no effect of the 3'NTR on IRES translation efficiency was observed, even in the presence of HCV proteins. These data demonstrate that HCV translation is not modulated by the viral genomic 3'NTR sequence, even in the presence of HCV structural or non-structural proteins.

3' Untranslated Regions↗
PubMed2005

Redesigning symmetry-related "mini-core" regions of FGF-1 to increase primary structure symmetry: thermodynamic and functional consequences of structural symmetry.

Previous reports detailing mutational effects within the hydrophobic core of human acidic fibroblast growth factor (FGF-1) have shown that a symmetric primary structure constraint is compatible with a stably folded protein. In the present report, we investigate symmetrically related pairs of buried hydrophobic residues in FGF-1 (termed "mini-cores") that are not part of the central core. The effect upon the stability and function of FGF-1 mutations designed to increase primary structure symmetry within these "mini-core" regions was evaluated. At symmetry-related positions 22, 64, and 108, the wild-type protein contains either Tyr or Phe side chains. The results show that either residue can be readily accommodated at these positions. At symmetry-related positions 42, 83, and 130, the wild-type protein contains either Cys or Ile side chains. While positions 42 and 130 can readily accommodate either Cys or Ile side chains, position 83 is substantially destabilized by substitution by Ile. Tertiary structure asymmetry in the vicinity of position 83 appears responsible for the inability to accommodate an Ile side chain at this position, and is known to contribute to functional half-life. A mutant form of FGF-1 with enforced primary structure symmetry at positions 22, 64, and 108 (all Tyr) and 42, 83, and 130 (all Cys) is shown to be more stable than the reference FGF-1 protein. The results support the hypothesis that a symmetric primary structure within a symmetric protein superfold represents a solution to achieving a foldable, stable polypeptide, and highlight the role that function may play in the evolution of asymmetry within symmetric superfolds.

3T3 Cells↗
PubMed1999

Crystal structure analysis of a pentameric fungal and an icosahedral plant lumazine synthase reveals the structural basis for differences in assembly.

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, complexed with the inhibitor 5-nitroso-6-ribitylamino-2,4-pyrimidinedione, from spinach and the fungus Magnaporthe grisea to 3.3 and 3.1 A resolution, respectively. The overall structure of the subunit and the mode of inhibitor binding are very similar in these enzyme species. The core of the subunit consists of a four-stranded parallel beta-sheet sandwiched between two helices on one side and three helices on the other. The packing of the five subunits in the pentameric M. grisea lumazine synthase is very similar to the packing in the pentameric substructures in the icosahedral capsid of the plant enzyme. Two structural features can be correlated to the differences in assembly. In the plant enzyme, the N-terminal beta-strand interacts with the beta-sheet of the adjacent subunit, thus extending the sheet from four to five strands. In fungal lumazine synthase, an insertion of two residues after strand beta1 results in a completely different orientation of this part of the polypeptide chain and this conformational difference prevents proper packing of the subunits at the trimer interface in the icosahedron. In the spinach enzyme, the beta-hairpin connecting helices alpha4 and alpha5 participates in the packing at the trimer interface of the icosahedron. Another insertion of two residues at this position of the polypeptide chain in the fungal enzyme disrupts the hydrogen bonding in the hairpin, and the resulting change in conformation of this loop also interferes with proper intrasubunit contacts at the trimer interface.

Amino Acid Sequence↗
PubMed1999

A test case for structure-based functional assignment: the 1.2 A crystal structure of the yjgF gene product from Escherichia coli.

The YER057c/YIL051c/YjgF protein family is a set of 24 full-length homologs, each approximately 130 residues in length, and each with no known function or relationship to proteins of known structure. To determine the function of this family, the structure of one member--the YjgF protein from Escherichia coli--was solved and refined at a resolution of 1.2 A. The YjgF molecule is a homotrimer with exact threefold symmetry. Its tertiary and quaternary structures are related to that of Bacillus subtilis chorismate mutase, although their active sites are completely different. The YjgF protein has an active site curiously similar to protein tyrosine phosphatases, including a covalently modified cysteine, but it is unlikely to be functionally related. The lessons learned from this attempt to deduce function from structure may be useful to future projects in structural genomics.

Amino Acid Sequence↗
PubMed1977

Predicted secondary structure of snake venom toxins from their primary structures.

We have predicted the secondary structure of 38 snake venom toxins using the method of Chou and Fasman. Our predictions indicate that beta-chain and random coil structures predominate in these proteins. The conformations of long neurotoxins, short neurotoxins and cytotoxins are less similar than previously believed. Cytotoxins contain 40--50% of beta-structure and they form a notably homogeneous group. Short neurotoxins contain less beta-structure (13--30%) and more random coil than cytotoxins, and they also form a more heterogeneous group in terms of secondary structure. The characteristics of long neurotoxins are intermediate to the above mentioned groups. Experimental evidence supporting these propositions is discussed.

Amino Acid Sequence↗
PubMed2006

The crystal structure of a plant 2C-methyl-D-erythritol 4-phosphate cytidylyltransferase exhibits a distinct quaternary structure compared to bacterial homologues and a possible role in feedback regulation for cytidine monophosphate.

The homodimeric 2C-methyl-D-erythritol 4-phosphate cytidylyltransferase contributes to the nonmevalonate pathway of isoprenoid biosynthesis. The crystal structure of the catalytic domain of the recombinant enzyme derived from the plant Arabidopsis thaliana has been solved by molecular replacement and refined to 2.0 A resolution. The structure contains cytidine monophosphate bound in the active site, a ligand that has been acquired from the bacterial expression system, and this observation suggests a mechanism for feedback regulation of enzyme activity. Comparisons with bacterial enzyme structures, in particular the enzyme from Escherichia coli, indicate that whilst individual subunits overlay well, the arrangement of subunits in each functional dimer is different. That distinct quaternary structures are available, in conjunction with the observation that the protein structure contains localized areas of disorder, suggests that conformational flexibility may contribute to the function of this enzyme.

Amino Acid Sequence↗
PubMed1996

Bridging the protein sequence-structure gap by structure predictions.

The problem of accurately predicting protein three-dimensional structure from sequence has yet to be solved. Recently, several new and promising methods that work in one, two, or three dimensions have invigorated the field. Modeling by homology can yield fairly accurate three-dimensional structures for approximately 25% of the currently known protein sequences. Techniques for cooperatively fitting sequences into known three-dimensional folds, called threading methods, can increase this rate by detecting very remote homologies in favorable cases. Prediction of protein structure in two dimensions, i.e. prediction of interresidue contacts, is in its infancy. Prediction tools that work in one dimension are both mature and generally applicable; they predict secondary structure, residue solvent accessibility, and the location of transmembrane helices with reasonable accuracy. These and other prediction methods have gained immensely from the rapid increase of information in publicly accessible databases. Growing databases will lead to further improvements of prediction methods and, thus, to narrowing the gap between the number of known protein sequences and known protein structures.

Amino Acid Sequence↗
PubMed1998

Tertiary structural models of human interleukin-6 and evaluation by comparison with X-ray and NMR structures.

Tertiary structure models of interleukin-6 were constructed using a routine prediction method based on the X-ray crystal structures of granulocyte colony-stimulating factor (GCSF) and leukemia inhibitory factor (LIF). Those models were evaluated using a sequence-structure compatibility (3D-1D) method program Compass and a limited amount of NMR distance information when it was concluded that the model based on GCSF (IBGC) was preferable to that from LIF (Sumikawa et al., FEBS Lett., 404, 234 (1997)). We evaluated the quality of this model (IBGC) by comparing with X-ray (Somers et al., EMBO., 16, 989 (1997)) and NMR (Xu et al., J. Mol. Biol., 268, 468 (1997)) structures. Consequently, normal mode calculations were carried out for this model, giving conformation fluctuations similar to the C alpha deviation pattern between X-ray and NMR structures.

Amino Acids↗
PubMed2006

Structure-function analysis of tritrpticin analogs: potential relationships between antimicrobial activities, model membrane interactions, and their micelle-bound NMR structures.

Tritrpticin is a member of the cathelicidin family of antimicrobial peptides. Starting from its native sequence (VRRFPWWWPFLRR), eight synthetic peptide analogs were studied to investigate the roles of specific residues in its biological and structural properties. This included amidation of the C-terminus paired with substitutions of its cationic and Phe residues, as well as the Pro residues that are important for its two-turn micelle-bound structure. These analogs were determined to have a significant antimicrobial potency. In contrast, two other peptide analogs, those with the three Trp residues substituted with either Phe or Tyr residues are not highly membrane perturbing, as determined by leakage and flip-flop assays using fluorescence spectroscopy. Nevertheless the Phe analog has a high activity; this suggests an intracellular mechanism for antimicrobial activity that may be part of the overall mechanism of action of native tritrpticin as a complement to membrane perturbation. NMR experiments of these two Trp-substituted peptides showed the presence of multiple conformers. The structures of the six remaining Trp-containing analogs bound to dodecylphosphocholine micelles showed major, well-defined conformations. These peptides are membrane disruptive and show a wide range in hemolytic activity. Their micelle-bound structures either retain the typical turn-turn structure of native tritrpticin or have an extended alpha-helix. This work demonstrates that closely related antimicrobial peptides can often have remarkably altered properties with complex influences on their biological activities.

Amino Acid Substitution↗
PubMed2000

Structure and structure-function studies of lipid/plasmid DNA complexes.

Recent synchrotron-based X-ray diffraction studies have enabled us to comprehensively solve the self-assembled structures in mixtures of cationic liposomes (CLs) complexed with linear lambda-DNA. In one case the CL-DNA complexes were found to consist of a higher ordered multilamellar structure (labeled L(alpha)C with DNA sandwiched between cationic bilayer membranes. The membrane charge density is found to control the DNA interaxial spacing with high densities leading to high DNA compaction between lipid bilayers. A second self-assembled structure (labeled H(II)C) consists of linear DNA strands coated by cationic lipid monolayers and arranged on a 2D hexagonal lattice. In this paper we report on a combined X-ray diffraction and optical microscopy study of CLs complexed with functional supercoiled plasmid DNA. We describe the self-assembled structures in cell culture medium for both a high transfectant complex (DOTAP/DOPE, phiDOPE = 0.72) and a low transfectant complex (DOTAP/DOPC, (phiDOPC = 0.72). Fluorescence optica microscopy shows two distinct interactions between these two types of complexes and mouse fibroblast L-cells, demonstrating the existence of a correlation between structure and transfection efficiency.

Animals↗
PubMed1992

[PAF-antagonists with phospholipid structure. 4. Alkylcarbamoylphospholipids with heteroarene and heterocyclase head groups and variation of the P-N-distance; synthesis, characterization and structure-activity relationship].

A series of 11 PAF-analogues, structurally modified in position 1 (alkylcarbamoyloxy), position 2 (n-propyl), and position 3 (polar head group) were synthesized, and the inhibitory potencies on human blood platelets in vitro was evaluated. Investigations of structure-activity relationships revealed, that the PAF antagonist activity is strongly influenced by the chain length of the alkylcarbamoyl residue and the structure of the polar head group. Derivatives with pentadecyl and octadecylcarbamoyl structure emerged effective inhibitors. The best activity was observed by dimethylaminopyridinium, analogues with a P-N distance of 3 or 4 methylene groups and pentadecyl or octadecylcarbamoyl structure (IC50 = 1.0-1.6 mumol/l).

Blood Platelets↗
PubMed1991

Atomic structure of ferredoxin-NADP+ reductase: prototype for a structurally novel flavoenzyme family.

The three-dimensional structure of spinach ferredoxin-NADP+ reductase (NADP+, nicotinamide adenine dinucleotide phosphate) has been determined by x-ray diffraction at 2.6 angstroms (A) resolution and initially refined to an R factor of 0.226 at 2.2 A resolution. The model includes the flavin-adenine dinucleotide (FAD) prosthetic group and the protein chain from residue 19 through the carboxyl terminus at residue 314 and is composed of two domains. The FAD binding domain (residues 19 to 161) has an antiparallel beta barrel core and a single alpha helix for binding the pyrophosphate of FAD. The NADP binding domain (residues 162 to 314) has a central five-strand parallel beta sheet and six surrounding helices. Binding of the competitive inhibitor 2'-phospho-AMP (AMP, adenosine monophosphate) places the NADP binding site at the carboxyl-terminal edge of the sheet in a manner similar to the nucleotide binding of the dehydrogenase family. The structures reveal the key residues that function in cofactor binding and the catalytic center. With these key residues as a guide, conclusive evidence is presented that the ferredoxin reductase structure is a prototype for the nicotinamide dinucleotide and FAD binding domains of the enzymes NADPH-cytochrome P450 reductase, NADPH-sulfite reductase, NADH-cytochrome b5 reductase, and NADH-nitrate reductase. Thus this structure provides a structural framework for the NADH- or NADPH-dependent flavoenzyme parts of five distinct enzymes involved in photosynthesis, in the assimilation of inorganic nitrogen and sulfur, in fatty-acid oxidation, in the reduction of methemoglobin, and in the metabolism of many pesticides, drugs, and carcinogens.

Adenosine Diphosphate↗