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At least 991 records · Page 55Linked to original sources
PubMed2004

The identification of novel RNA structural motifs using COMPADRES: an automated approach to structural discovery.

Recurring RNA structural motifs are important sites of tertiary interaction and as such, are integral to RNA macromolecular structure. Although numerous RNA motifs have been classified and characterized, the identification of new motifs is of great interest. In this study, we discovered four new conformationally recurring motifs: the pi-turn, the Omega-turn, the alpha-loop and the C2'-endo mediated flipped adenosine motif. Not only do they have complex and interesting structures, but they participate in contacts of high biological significance. In a first for the RNA field, new motifs were discovered by a fully automated algorithm. This algorithm, COMPADRES, utilized a reduced representation of the RNA backbone and was highly successful at discerning unique structural relationships. This study also shows that recurring RNA substructures are not necessarily accompanied by consistent primary or secondary structure.

Adenosine↗
PubMed2006

NMR solution structure of the major G-quadruplex structure formed in the human BCL2 promoter region.

BCL2 protein functions as an inhibitor of cell apoptosis and has been found to be aberrantly expressed in a wide range of human diseases. A highly GC-rich region upstream of the P1 promoter plays an important role in the transcriptional regulation of BCL2. Here we report the NMR solution structure of the major intramolecular G-quadruplex formed on the G-rich strand of this region in K+ solution. This well-defined mixed parallel/antiparallel-stranded G-quadruplex structure contains three G-tetrads of mixed G-arrangements, which are connected with two lateral loops and one side loop, and four grooves of different widths. The three loops interact with the core G-tetrads in a specific way that defines and stabilizes the overall G-quadruplex structure. The loop conformations are in accord with the experimental mutation and footprinting data. The first 3-nt loop adopts a lateral loop conformation and appears to determine the overall folding of the BCL2 G-quadruplex. The third 1-nt double-chain-reversal loop defines another example of a stable parallel-stranded structural motif using the G3NG3 sequence. Significantly, the distinct major BCL2 promoter G-quadruplex structure suggests that it can be specifically involved in gene modulation and can be an attractive target for pathway-specific drug design.

DNA↗
PubMed2005

Investigating the structure of craving using structural equation modeling in analysis of the obsessive-compulsive drinking scale: a multinational study.

BACKGROUND: Currently, there is no agreement among researchers on the definition of craving and its underlying theoretical model. The Obsessive-Compulsive Drinking Scale (OCDS) seems to measure certain aspects of craving, but its theoretical basis remains unclear. The aim of this study was to investigate the structure of alcohol craving, using OCDS data. METHODS: OCDS data from four studies were pooled to obtain a large and heterogeneous sample of 505 participants. All participants were treatment-seeking alcoholics meeting DSM-IV criteria for alcohol dependence. The factor structures of the OCDS previously found were evaluated using confirmatory factor analyses. The goodness of fit of these solutions was compared with those of alternative causal models: an obsessive-compulsive disorder model, an inhibition model, and a cognitive-behavioral model. These alternative models were based on modern theories about craving and were tested in the OCDS data, using structural equation modeling. In this way, the current study replaced simple correlational analysis by a more sophisticated causal way of analyzing the underlying structure of the OCDS items. The best fitting model was selected by comparing the mean discrepancy between the implied and observed matrices of the models. RESULTS: The data showed that the previously reported factor structures had to be rejected. Also, the inhibition model and obsessive-compulsive disorder model did not fit the data. The cognitive-behavioral model showed encouraging fit. Optimizing strategies were applied to further improve the fit of this model, which resulted in a model with close fit to the data. CONCLUSIONS: The causal cognitive-behavioral model proved to be superior. It showed that the OCDS contains many items that do not represent the core concept of craving but instead are indicators for the consequences of craving. From this model, it seems that craving, in a narrow sense, can be reliably assessed with only five items of the OCDS.

Adult↗
PubMed1990

Tertiary structural constraints on protein evolutionary diversity: templates, key residues and structure prediction.

The pattern of residue substitution in divergently evolving families of globular proteins is highly variable. At each position in a fold there are constraints on the identities of amino acids from both the three-dimensional structure and the function of the protein. To characterize and quantify the structural constraints, we have made a comparative analysis of families of homologous globular proteins. Residues are classified according to amino acid type, secondary structure, accessibility of the sidechain, and existence of hydrogen bonds from sidechain to other sidechains or peptide carbonyl or amide functions. There are distinct patterns of substitution especially where residues are both solvent inaccessible and hydrogen bonded through their sidechains. The patterns of residue substitution can be used to construct templates or to identify 'key' residues if one or more structures are known. Conversely, analysis of conversation and substitution across a large family of aligned sequences in terms of substitution profiles can allow prediction of tertiary environment or indicate a functional role. Similar analyses can be used to test the validity of putative structures if several homologous sequences are available.

Amino Acid Sequence↗
PubMed1999

Two non-structural rotavirus proteins, NSP2 and NSP5, form viroplasm-like structures in vivo.

In rotavirus-infected cells, the non-structural proteins NSP5 and NSP2 localize in complexes called viroplasms, where replication and assembly occur. Recently, we have demonstrated direct interaction of NSP5 with NSP2, and as a consequence of that, up-regulation of NSP5 hyperphosphorylation. To investigate a possible structural role for the NSP2-NSP5 interaction, we analysed the cytoplasmic distribution of the two proteins in transfected cells by immunofluorescence using specific antibodies. Here we report that NSP2 and NSP5 can drive the formation of viroplasm-like structures (VLS) in the absence of other rotaviral proteins and rotavirus replication. Several NSP5 deletion mutants were constructed and expressed in combination with NSP2. Both the N- and C-terminal domains of NSP5 were found to be essential for VLS formation. Only one mutant, with an internal deletion of residues 81-130, was able to interact with NSP2 to form VLS. Analysis of the phosphorylation capacity of the different mutants in vivo indicated that hyperphosphorylation of NSP5 is necessary, but not sufficient, for VLS formation. Our results suggest a role for the non-structural protein NSP5 in the structure of viroplasms mediated by its interaction with NSP2.

Animals↗
PubMed1999

Three-phase structure invariants and structure factors determined with the quantitative convergent-beam electron diffraction method.

Quantitative convergent-beam electron diffraction is used to determine structure factors and three-phase structure invariants. The refinements are based on centre-disc intensities only. An algorithm for param-eter-sensitive pixel sampling of experimental intensities is implemented in the refinement procedure to increase sensitivity and computer speed. Typical three-beam effects are illustrated for the centrosymmetric case. The modified refinement method is applied to determine amplitudes and three-phase structure invariants in noncentrosymmetric InP. The accuracy of the results is shown to depend on the choice of the initial parameters in the refinement. Even unrealistic starting assumptions and incorrect temperature factor lead to stable results for the structure invariant. The examples show that the accuracy varies from 1 to 10 degrees in the electron three-phase invariants determined and from 0.5 to 5% for the amplitudes. Individual phases could not be determined in the present case owing to spatial intensity correlations between phase-sensitive pixels. However, for the three-phase structure invariant, stable solutions were found.

Journal Article↗
PubMed2001

Structures of furanosides: geometrical analysis of low-temperature X-ray and neutron crystal structures of five crystalline methyl pentofuranosides.

Crystal structures of all five crystalline methyl D-pentofuranosides, methyl alpha-D-arabinofuranoside (1), methyl beta-D-arabinofuranoside (2), methyl alpha-D-lyxofuranoside (3), methyl beta-D-ribofuranoside (4) and methyl alpha-D-xylofuranoside (5) have been determined by means of cryogenic X-ray and neutron crystallography. The neutron diffraction experiments provide accurate, unbiased H-atom positions which are especially important because of the critical role of hydrogen bonding in these systems. This paper summarizes the geometrical and conformational parameters of the structures of all five crystalline methyl pentofuranosides, several of them reported here for the first time. The methyl pentofuranoside structures are compared with the structures of the five crystalline methyl hexopyranosides for which accurate X-ray and neutron structures have been determined. Unlike the methyl hexopyranosides, which crystallize exclusively in the C(1) chair conformation, the five crystalline methyl pentofuranosides represent a very wide range of ring conformations.

Journal Article↗
PubMed2002

The Cambridge Structural Database: a quarter of a million crystal structures and rising.

The Cambridge Structural Database (CSD) now contains data for more than a quarter of a million small-molecule crystal structures. The information content of the CSD, together with methods for data acquisition, processing and validation, are summarized, with particular emphasis on the chemical information added by CSD editors. Nearly 80% of new structural data arrives electronically, mostly in CIF format, and the CCDC acts as the official crystal structure data depository for 51 major journals. The CCDC now maintains both a CIF archive (more than 73,000 CIFs dating from 1996), as well as the distributed binary CSD archive; the availability of data in both archives is discussed. A statistical survey of the CSD is also presented and projections concerning future accession rates indicate that the CSD will contain at least 500,000 crystal structures by the year 2010.

Journal Article↗
PubMed2002

Simulated annealing structure solution of a new phase of dicalcium silicate Ca(2)SiO(4) and the mechanism of structural changes from alpha-dicalcium silicate hydrate to alpha(L)'-dicalcium silicate via the new phase.

A new phase of dicalcium silicate (Ca(2)SiO(4)) was formed by heating alpha-dicalcium silicate hydrate [alpha-Ca(2)(SiO(4)H)OH = alpha-C(2)SH] at temperatures of approximately 663-763 K, and it was transformed into alpha(L)'-Ca(2)SiO(4) (= alpha(L)'-C(2)S) above approximately 1193 K. The crystal structure of the new phase (hereafter called x-C(2)S) has been determined by simulated annealing and refined by the Rietveld method using synchrotron radiation powder diffraction data. The structure consists of isolated SiO(4) tetrahedra and a three-dimensional CaO(n) polyhedral network, forming a new structural type of dicalcium silicate. A structural change from alpha-C(2)SH to x-C(2)S is compelled by large displacements of SiO(4) tetrahedra, accompanied by dehydration, in the direction perpendicular to the two-dimensional Ca(O,OH)(n) polyhedral network in alpha-C(2)SH. With increasing temperature, sizes of CaO(n) polyhedra in x-C(2)S become too large to confine Ca atoms at the sixfold to eightfold coordination sites. Then the structure of x-C(2)S is transformed into alpha(L)'-C(2)S, having eightfold to tenfold coordination sites for the Ca atoms.

Journal Article↗
PubMed2003

Space group and atomic structure determination of a nano-sized ordered phase derived from a f c c structure in maraging steel 12Cr-9Ni-4Mo-2Cu using transmission electron microscopy.

The unique properties of maraging steel Sandvik 1RK91 were attributed to unique precipitation: a nano-sized L phase in addition to the quasi-crystalline R' phase, which differs from any precipitation system in conventional maraging steels. The L phase was observed after ageing at either 748 or 823 K. It has flake morphology with dimensions approximately 100 x 500 x 500 A. In the present study the structure of the L phase was examined using convergent-beam electron diffraction (CBED), energy-dispersive X-ray analysis (EDX) and high-resolution electron microscopy (HREM). The L phase could be described as Ti(19)Fe(9)Mo(9)Al(8)Cr(5)Ni(50) or simply M(50)Ni(50) (M = Ti, Fe, Mo, Al and Cr). The L phase is isostructural to FeNi. Its crystal structure was determined to have the ordered structure of the uAu-I type (L1(0), P4/mmm, a = 3.52, c = 3.63 A and Z = 2) with two Ni atoms at (1/2) 0 (1/2) and 0 (1/2) (1/2), and two M atoms at 0 0 0 and (1/2) (1/2) 0. The crystal structure of the L phase can also be described using a primitive tetragonal cell and lattice parameters: a = 2.49 and c = 3.63 A, Z = 1. The Volume of the primitive tetragonal unit cell is 22.5 A(3) and the density is approximately 6.98 g cm(-3). The present study has demonstrated the possibility of determining the structure of an extremely small crystal by utilizing the information from CBED, EDX analysis and HREM.

Journal Article↗
PubMed2006

Structural complexity in minerals: twinning, polytypism and disorder in the crystal structure of polybasite, (Ag,Cu)16(Sb,As)2S11.

The crystal structures of 222- and 221-polybasite [(Ag,Cu)(16)(Sb,As)(2)S(11)] crystals have been solved and refined by means of X-ray diffraction data (collected at 100 and 120 K, respectively) from twinned crystals. Both structures consist of the stacking of [(Ag,Cu)(6)Sb(2)S(7)](2-) and [Ag(9)CuS(4)](2+) module layers in which Sb forms isolated SbS(3) pyramids typically occurring in sulfosalts; copper links two S atoms in a linear coordination and silver occupies sites with coordination ranging from quasi-linear to almost tetrahedral. An Ag --> Cu substitution in the [(Ag,Cu)(6)Sb(2)S(7)](2-) module layer is observed in both structures, the substitution amount being larger in the 221- than in the 222-polybasite. A pattern of the possible mechanism regulating the type of unit cell that is stabilized is proposed: starting from the hypothetical stoichiometric and fully ordered Ag(15)CuSb(2)S(11) 222-polybasite structure, with a low C2/c monoclinic symmetry and a large 222 supercell, the disorder introduced by the substitution of Cu for Ag increases the symmetry with a cell reduction along the c axis yielding the 221 supercell and a trigonal crystal system. A further increase of the substitution gives rise to a folding of the cell along the a and b axes and the 111-pearceite structure, space group P(bar)3m1.

Journal Article↗
PubMed2000

How do the x-ray structure and the NMR structure of FMN-binding protein differ?

The crystal structure of FMN-binding protein (FMN-bp) from Desulfovibrio vulgaris Miyazaki F was solved by the multiple isomorphous replacement method and refined to an R factor of 15.1% at 1.3 A resolution. FMN-bp exists in a dimeric form in the crystal, in contrast to the monomeric structure determined by NMR. R.m.s. deviations between the crystal structure and the solution structure are more than 2 A, which implies significant differences. There are some hydrophobic residues in the interface between the two monomers. In particular, Leu122 in the C-terminus has a close contact with the o-xylene moiety of FMN, while solvent molecules may cover the o-xylene moiety in the solution structure.

Bacterial Proteins↗
PubMed2004

Structure of 9-amino-[N-(2-dimethylamino)propyl]acridine-4-carboxamide bound to d(CGTACG)(2): a comparison of structures of d(CGTACG)(2) complexed with intercalatorsin the presence of cobalt.

The structure of the complex formed between 9-amino-[N-(2-dimethylamino)propyl]acridine-4-carboxamide and d(CGTACG)(2) has been refined to a resolution of 1.55 A. The complex crystallized in space group C222. An asymmetric unit comprises two strands of DNA, one disordered drug molecule, two cobalt(II) ions, two magnesium ions and 32 water molecules. The DNA helices stack in continuous columns, with their four central base pairs adopting a B-like motif. The terminal G.C base pairs engage in different interactions. At one end of the duplex there is a CpG dinucleotide overlap modified by ligand intercalation and terminal cytosine exchange between symmetry-related duplexes. An intercalation complex is formed involving four DNA duplexes, four disordered ligand molecules and two pairs of base tetrads. The other end of the DNA is frayed, with the terminal guanine lying in the minor groove of the next duplex in the column. The structure is stabilized by guanine N7-cobalt(II) coordination. The structure is compared with previously published isomorphous structures of d(CGTACG)(2) complexed with intercalators in the presence of cobalt and it is concluded that the formation of this crystal form is primarily determined by DNA-DNA interactions and packing forces, rather than by special interactions between the ligand and the DNA. Given the nature of the ligands found in these complexes, the relevance of the quadruplex structure to the biological activity of those agents, known to be topoisomerase poisons, is questioned.

Acridines↗
PubMed2005

The structure of F420-dependent methylenetetrahydromethanopterin dehydrogenase: a crystallographic 'superstructure' of the selenomethionine-labelled protein crystal structure.

The diffraction pattern of native protein crystals of F(420)-dependent methylenetetrahydromethanopterin dehydrogenase from Methanopyrus kandleri shows weak additional reflections compared with the selenomethionine-labelled protein crystals, indicating a doubled c unit-cell parameter. These reflections indicate small reorientations of the hexameric structural units, breaking the translational symmetry. TLS refinement of the selenomethionine-labelled protein structure at 1.55 A resolution revealed an anisotropic rigid-body libration of the hexameric units. The anisotropy is consistent with the static reorientation in the native protein crystals. These results are discussed as related to the crystal packing. The relation between the two structures suggests an analogy to structural changes during certain kinds of phase transitions that have been well studied in inorganic structural chemistry.

Crystallography, X-Ray↗
PubMed2005

Three-dimensional structure determination of proteins related to human health in their functional context at The Israel Structural Proteomics Center (ISPC). This paper was presented at ICCBM10.

The principal goal of the Israel Structural Proteomics Center (ISPC) is to determine the structures of proteins related to human health in their functional context. Emphasis is on the solution of structures of proteins complexed with their natural partner proteins and/or with DNA. To date, the ISPC has solved the structures of 14 proteins, including two protein complexes. It has adopted automated high-throughput (HTP) cloning and expression techniques and is now expressing in Escherichia coli, Pichia pastoris and baculovirus, and in a cell-free E. coli system. Protein expression in E. coli is the primary system of choice in which different parameters are tested in parallel. Much effort is being devoted to development of automated refolding of proteins expressed as inclusion bodies in E. coli. The current procedure utilizes tagged proteins from which the tag can subsequently be removed by TEV protease, thus permitting streamlined purification of a large number of samples. Robotic protein crystallization screens and optimization utilize both the batch method under oil and vapour diffusion. In order to record and organize the data accumulated by the ISPC, a laboratory information-management system (LIMS) has been developed which facilitates data monitoring and analysis. This permits optimization of conditions at all stages of protein production and structure determination. A set of bioinformatics tools, which are implemented in our LIMS, is utilized to analyze each target.

Automation↗
PubMed1995

TEM1 beta-lactamase structure solved by molecular replacement and refined structure of the S235A mutant.

beta-Lactamases are bacterial enzymes which catalyse the hydrolysis of the beta-lactam ring of penicillins, cephalosporins and related compounds, thus inactivating these antibiotics. The crystal structure of the TEM1 beta-lactamase has been determined at 1.9 A resolution by the molecular-replacement method, using the atomic coordinates of two homologous beta-lactamase refined structures which show about 36% strict identity in their amino-acid sequences and 1.96 A r.m.s. deviation between equivalent Calpha atoms. The TEM1 enzyme crystallizes in space group P2(1)2(1)2(1) and there is one molecule per asymmetric unit. The structure was refined by simulated annealing to an R-factor of 15.6% for 15 086 reflections with I >/= 2sigma(I) in the resolution range 5.0-1.9 A. The final crystallographic structure contains 263 amino-acid residues, one sulfate anion in the catalytic cleft and 135 water molecules per asymmetric unit. The folding is very similar to that of the other known class A beta-lactamases. It consists of two domains, the first is formed by a five-stranded beta-sheet covered by three alpha-helices on one face and one alpha-helix on the other, the second domain contains mainly alpha-helices. The catalytic cleft is located at the interface between the two domains. We also report the crystallographic study of the TEM S235A mutant. This mutation of an active-site residue specifically decreases the acylation rate of cephalosporins. This TEM S235A mutant crystallizes under the same conditions as the wild-type protein and its structure was refined at 2.0 A resolution with an R value of 17.6%. The major modification is the appearance of a water molecule near the mutated residue, which is incompatible with the OG 235 present in the wild-type enzyme, and causes very small perturbations in the interaction network in the active site.

Journal Article↗
PubMed2001

Local structures of mechanically alloyed Fe100-xCux solid solutions studied by X-ray absorption fine structure.

The local structures of the immiscible Fe(100-x)Cu(x) alloys (x= 0, 10, 20, 40, 60, 80 and 100) produced by mechanical alloying have been investigated by XAFS. For the Fe(100-x)Cu(x) (x > or = 40) solid solutions, the local structures around Fe atoms change from bcc structure to fcc one and the Cu atoms maintain the original coordination geometry after milling for 160 hours. On the contrary, the local structures around Cu atoms in both of Fe80Cu20 and Fe90Cu10 alloys appear a transition from fcc to bcc structure. We found that the Debye-waller factor sigma of fcc Fe-Cu phase is larger than that of bcc Fe-Cu phase, and the sigma (0.099 A) around Fe atoms is larger than that (0.089 A) of Cu in the Fe(100-x)Cu(x) (x > or = 40) solid solutions. This suggests that the mechanically alloyed Fe(100-x)Cu(x) supersaturated solid solution is not a homogeneous alloy, and consists of Fe-rich and Cu-rich regions for various compositions. A possible mechanism for bcc-to-fcc and fcc-to-bcc changes in Fe(100-x)Cu(x) solid solutions is discussed in relation to the interdiffusion and transition induced by the ball milling.

Journal Article↗
PubMed2002

Extension of a local backbone description using a structural alphabet: a new approach to the sequence-structure relationship.

Protein Blocks (PBs) comprise a structural alphabet of 16 protein fragments, each 5 Calpha long. They make it possible to approximate and correctly predict local protein three-dimensional (3D) structures. We have selected the 72 most frequent sequences of five PBs, which we call Structural Words (SWs). Analysis of four different protein data banks shows that SWs cover 92% of the amino acids in them and provide a good structural approximation for residues (i.e., sequences) 9 Calpha long. We present most of them in a simple network that describes 90% of the overall residues and, interestingly, includes more than 80% of the amino acids present in coils. Analysis of the network shows the specificity and quality of the 3D descriptions as well as a new type of relation between local folds and amino acid distribution. The results show that the 3D structure of these protein data banks can be easily described by a combination of subgraphs included in the network. Finally, a Bayesian probabilistic approach improved the prediction rate by 4%.

Amino Acid Sequence↗