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PubMed2003

Design and structure-based study of new potential FKBP12 inhibitors.

Based on the structure of FKBP12 complexed with FK506 or rapamycin, with computer-aided design, two neurotrophic ligands, (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-Leucine ethyl ester and (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-phenylalanine benzyl ester, were designed and synthesized. Fluorescence experiments were used to detect the binding affinity between FKBP12 and these two ligands. Complex structures of FKBP12 with these two ligands were obtained by x-ray crystallography. In comparing FKBP12-rapamycin complex and FKBP12-FK506 complex as well as FKBP12-GPI-1046 solution structure with these new complexes, significant volume and surface area effects and obvious contact changes were detected which are expected to cause their different binding energies-showing these two novel ligands will become more effective neuron regeneration drugs than GPI-1046, which is currently undergoing phase II clinical trail as a neurotrophic drug. Analysis of volume and surface area effects also gives a new clue for structure-based drug design.

Binding Sites↗
PubMed1998

Measures of complexity for cancellous bone.

The problem of quantifying the structure of cancellous bone has been addressed in the past by histomorphometry and more recently by imaging techniques using X-ray attenuation. The current approaches compute and describe parts of the construction of the trabecular net. We developed a new technique which quantifies cancellous bone of human lumbar vertebrae as a whole. The interactions, transactions, and interrelationships of all parts of the structural composition of the trabeculae are accounted for and quantified. The method is based on the concept of structural complexity within the framework of nonlinear dynamics. The methodology was developed by using axial high resolution computed tomography images. The technique was transferred to quantitative computed tomography images and is based on the non-invasive assessment of 50 human L3 specimens. The value of Houndsfield units per pixel representing trabecular bone of the vertebrae was transformed into color-encoded and alphabet-encoded symbols. The procedure of transformation of the X-ray attenuation pixels into symbols was necessary as a basis on which measures of complexity were introduced to assess the composition of symbols within the images. The development of a generalization of symbolic dynamics, a mathematical method, to work with two-dimensional images was a prerequisite. The results of this study demonstrate that the structural composition of cancellous bone declines more rapidly than bone mineral density during the loss of bone. This outcome strongly suggests an exponential relationship between bone mineral density and the architectural composition of cancellous bone. Normal trabecular bone has a complex ordered structure. The structural composition during the osteopenic phase of bone loss is characterized by lower structural complexity and a significantly higher level of architectural disorder. A high grade of osteoporosis leads again to an ordered structure, although its structural complexity is minimal.

Algorithms↗
PubMed1978

[Role of sterol structure in complex formation with polyene antibiotics].

The capacity of sterols of different structure being components of artificial bilayer lipid membranes for formation of complexes with polyenic antibiotics, such as amphotericin B, nistatin and levorin was studied. It was shown that sterols delat 5,7-dienic systemin ring B, ergosterol and cholesta-5,7,22-trien 3 beta-ol had the highest affinity to all the 3 antibiotics, while sterols with one double bond in ring B, i. e. cholesterol and brassicasterol had less affinity and sterol without any double bonds in the molecule i.e. 5alpha cholestan 3beta-ol had the least affinity. It was supposed that delta 5,7-sterols had the highest affinity to polyens because of the fact that atoms C-5, C-6; C-7 and C-8 in ring B were practically situated in one plane in contrast to sterols with completely saturated ring B situated in the "conformation chair". Because of this interaction between delta 5,7-sterol ring B and the same flat polyenic site of the antibiotic molecule is sterically most firm since maximum contact is possible between two planes. It was noted that affinity of sterol to the polyenic antibiotics was higher if there were a double bond at 22-23 and methyl group at C-24 in the sterol side chain.

Anti-Bacterial Agents↗
PubMed2000

Experimental validations of the HELS method for reconstructing acoustic radiation from a complex vibrating structure

This paper presents experimental validations of the Helmholtz Equation Least Squares (HELS) method [Wang and Wu, J. Acoust. Soc. Am. 102, 2020-2032 (1997); Wu and Wang, U.S. Patent Number 5712805 (1998); Wu, J. Acoust. Soc. Am. 107, 2511-2522 (2000)] on reconstruction of the radiated acoustic pressures from a complex vibrating structure. The structure under consideration has geometry and dimensions similar to those of a real passenger vehicle front end. To simulate noise radiation from a vehicle, a high fidelity loudspeaker installed inside the structure at the location of the engine is employed to generate both random and harmonic acoustic excitations. The radiated acoustic pressures are measured over a finite planar surface above the structure by a microphone. The measured data are taken as input to the HELS formulation to reconstruct the acoustic pressures on the top surface of the structure as well as in the field. The reconstructed acoustic pressures are then compared with measured ones at the same locations. Also shown are comparisons of the reconstructed and measured acoustic pressure spectra at various locations on the surface. Results show that satisfactory reconstruction can be obtained on the top surface of the structure subject to both random and harmonic excitations. Moreover, the more measurements and the closer their distances to the source surface, the more accurate the reconstruction. The efficiency of the HELS method may decrease with increasing of the excitation frequency. This high frequency difficulty is inherent in all expansion theories.

Journal Article↗
PubMed1985

Consequences of serial cortical, hippocampal, and thalamic lesions and of different lengths of overtraining on the acquisition and retention of learning tasks.

The ability of the rat brain to acquire or to retain specific learning tasks was tested under conditions of multiple lesions and widely different amounts of practice. Lesion targets were (a) the medial prefrontal and cingulate cortex, (b) the anterior and mediodorsal thalamus, and (c) the dorsal and ventral hippocampus. Rats were divided into seven groups. The first group received lesions of all three structural complexes prior to training in a delayed alternation and an active avoidance task. Groups 2-4 received lesions in different combinations of two of the three structural complexes prior to task acquisition. Group 5 first learned both tasks and then received the medial cortical lesion; thereafter it was retrained to criterion. Then, the thalamic lesion was made, and relearning was tested a second time. Finally, the hippocampal region was damaged, and a last relearning test was given. Groups 6 and 7 also first acquired both tasks; however, after that, they received 240 (Group 6) or 1,280 (Group 7) trials of overtraining. Following this, all three structural complexes were given lesions serially before relearning of the two tasks was tested. Nine of the ten animals of Group 1 failed to acquire the alternation task, but all learned the avoidance task. In Groups 2-4, all rats acquired both tasks. Postoperatively, rats of Group 5 were inferior to those of Group 6 in both tasks, and rats of Group 7 were the most successful animals of the last three groups. These results question the assumption that serial lesions with intermittent training between lesions have beneficial effects, and they also stress the importance of task practice, that is, of behavioral experience. It is argued that prolonged training will lead to a widely distributed storage of information within the brain. The process of wide diffusion of information will, however, be disturbed (or at least retarded) by lesions made shortly after task acquisition or task reacquisition (as was the case for animals of Group 5).

Animals↗
PubMed2000

Complex band structure and tunneling through ferromagnet /Insulator /Ferromagnet junctions

We investigate the importance of metal-induced gap states for the tunneling of metal electrons through epitaxial insulator films. By introducing an imaginary part kappa to the wave vector in order to describe the decay of the wave function in the insulator, we obtain the complex band structure in the gap region. The spectrum of the decay parameters kappa is calculated for the semiconductors Si, Ge, GaAs, and ZnSe. In most cases, for large enough film thicknesses the tunneling is dominated by states of normal incidence on the interface. Possible exceptions are considered. Based on our conclusions, we discuss the spin-dependent tunneling in Fe/semiconductor/Fe (001) junctions.

Journal Article↗
PubMed2003

The omission of subject arguments in children with specific language impairment.

Ten children with specific language impairment (SLI) were compared to two groups of normally developing children for the production of grammatical subjects in sentences of varying length and argument structure complexity. The normal controls consisted of a group of younger children matched for mean length of utterance (MLU) and a group matched for chronological age. The participants were asked to produce sentences of varied argument structure complexity using a story completion task. The results indicated that both the children with SLI and the MLU controls omitted more subject arguments in the ditransitive sentences than in sentences with intransitive and ditransitive verbs. In addition, more children with SLI omitted subject arguments as linguistic complexity increased. This effect was not found for the normal age control children who never omitted subjects, regardless of increases in argument structure complexity. These results support the notion that grammatical errors in both children with SLI and their younger, normal counterparts may be due to problems with processing complex linguistic information rather than with limitations in linguistic knowledge.

Child↗
PubMed2006

In silico grouping of peptide/HLA class I complexes using structural interaction characteristics.

MOTIVATION: Classification of human leukocyte antigen (HLA) proteins into supertypes underpins the development of epitope-based vaccines with wide population coverage. Current methods for HLA supertype definition, based on common structural features of HLA proteins and/or their functional binding specificities, leave structural interaction characteristics among different HLA supertypes with antigenic peptides unexplored. METHODS: We describe the use of structural interaction descriptors for the analysis of 68 peptide/HLA class I crystallographic structures. Interaction parameters computed include the number of intermolecular hydrogen bonds between each HLA protein and its corresponding bound peptide, solvent accessibility, gap volume and gap index. RESULTS: The structural interactions patterns of peptide/HLA class I complexes investigated herein vary among individual alleles and may be grouped in a supertype dependent manner. Using the proposed methodology, eight HLA class I supertypes were defined based on existing experimental crystallographic structures which largely overlaps (77% consensus) with the definitions by binding motifs. This mode of classification, which considers conformational information of both peptide and HLA proteins, provides an alternative to the characterization of supertypes using either peptide or HLA protein information alone.

Alleles↗
PubMed2000

Sequencing of peach latent mosaic viroid variants from nine North American peach cultivars shows that this RNA folds into a complex secondary structure.

We sequenced 34 new peach latent mosaic viroid (PLMVd) variants isolated from nine different peach cultivars. This study provides the widest view of PLMVd diversity reported to date and includes the original characterization of North American variants, which cannot be differentiated from European sequences. PLMVd appears as a species in which each isolate is a complex mixture of RNAs. Analysis of base-pair covariations supports the hypothesis that PLMVd folds into a complex branched structure with the potential of including three new pseudoknots. The resulting "globular-like" structure is in contrast to the rod-like one adopted by most other viroids.

Base Sequence↗
PubMed2004

Crystal structure of transglutaminase 3 in complex with GMP: structural basis for nucleotide specificity.

Epidermal-type Transglutaminase 3 (TGase 3) is a Ca(2+)-dependent enzyme involved in the cross-linking of structural proteins required in the assembly of the cell envelope. We have recently shown that calcium-activated TGase 3, like TGase 2, can bind, hydrolyze, and is inhibited by GTP despite lacking structural homology with other GTP-binding proteins. Here we report the crystal structure determined at 2.0 A resolution of TGase 3 in complex with GMP to elucidate the structural features required for nucleotide recognition. Binding affinities for various nucleotides were found by fluorescence displacement to be as follows: guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) (0.4 microm), GTP (0.6 microm), GDP (1.0 microm), GMP (0.4 microm), and ATP (28.0 microm). Furthermore, we found that GMP binds as a reversible, noncompetitive inhibitor of TGase 3 transamidation activity, similar to GTPgammaS and GDP. A genetic algorithm similarity program (GASP) approach (virtual ligand screening) identified three compounds from the Lead Quest trade mark data base (Tripos Inc.) based on superimposition of GTPgammaS, GDP, and GMP guanine nucleotides from our crystal structures to generate the minimum align flexible fragment. These three were nucleotide analogs without a phosphate group containing the minimal binding motif for TGase 3 that includes a nucleoside recognition groove. Binding affinities were measured as follows: TP349915 (K(d) = 4.1 microm), TP395289 (K(d) = 38.5 microm), TP394305 (K(d) = 1.0 mm). Remarkably, these compounds do not inhibit but instead activate TGase 3 transamidation by about 10-fold. These results suggest that the nucleotide binding pocket in TGase 3 may be exploited to either enhance or inhibit the enzymatic activity as required for different therapeutic approaches.

Adenosine Triphosphate↗
PubMed1998

Probing the structure of complex macromolecular interactions by homolog specificity scanning: the P1 and P7 plasmid partition systems.

The P1 plasmid partition locus, P1 par, actively distributes plasmid copies to Escherichia coli daughter cells. It encodes two DNA sites and two proteins, ParA and ParB. Plasmid P7 uses a similar system, but the key macromolecular interactions are species specific. Homolog specificity scanning (HSS) exploits such specificities to map critical contact points between component macromolecules. The ParA protein contacts the par operon operator for operon autoregulation, and the ParB contacts the parS partition site during partition. Here, we refine the mapping of these contacts and extend the use of HSS to map protein-protein contacts. We found that ParB participates in autoregulation at the operator site by making a specific contact with ParA. Similarly, ParA acts in partition by making a specific contact with ParB bound at parS. Both these interactions involve contacts between a C-terminal region of ParA and the extreme N-terminus of ParB. As a single type of ParA-ParB complex appears to be involved in recognizing both DNA sites, the operator and the parS sites may both be occupied by a single protein complex during partition. The general HSS strategy may aid in solving the three-dimensional structures of large complexes of macromolecules.

Amino Acid Sequence↗
PubMed1987

Analysis of asparagine-linked oligosaccharide structures of chronic lymphocytic leukemia cells.

The asparagine-linked oligosaccharide structures of chronic lymphocytic leukemia cells (CLL) were studied by sequential lectin affinity chromatography. Glycopeptides were isolated from a Concanavalin A (ConA)-binding glycoprotein fraction prepared from a soluble CLL extract. This fraction, which contained 1.8% of the proteins present in the soluble extract, greater than 30 polypeptides revealed by SDS-PAGE analysis, and known cell surface antigens such as HLA-DR and p85 glycoprotein, must include a major proportion of the glycoproteins of the CLL cells. Glycopeptides were prepared by digestion with pronase, were separated into four pools (A-D) by Bio-Gel P-6 filtration and were radiolabeled by N-14C-acetylation. Glycopeptide pools C and D (0.45 less than Kd less than 0.77) were 95-100% bound to ConA-Sepharose and 7-12% bound to Lens culinaris (Lens)-Sepharose, but did not interact with any of the other lectins tested, suggesting major amounts of high mannose structures and minor amounts of fucosylated biantennary complex structures with terminal GlcNAc on the Man alpha 1-6 arm. Structures with greater than 3 branches were suggested for pools A and B (0 less than Kd less than 0.44) which were 34-65% unbound to ConA-Sepharose and 37-40% bound to Lens-Sepharose. Analysis of the ConA-unbound glycopeptides on RCA-Agarose before and after acid hydrolysis indicated variable amounts of terminal galactose and sialic acid residues. Major components of pool A were structures with terminal GlcNAc on all branches (22%) and fully sialylated structures (20%). In pool B, 20% of the radioactivity interacted with L-Phaseolus vulgaris agglutinin (PHA)-Agarose and with Ricinus communis (RCA)-Agarose, indicative of a fully galactosylated triantennary structure with branches at C-2 and C-6 of the Man alpha 1-6 arm. Half of the L-PHA-interacting material also bound to Lens-Sepharose, indicative of a core fucose residue. A fully galactosylated biantennary complex structure in pool A (13%) was identified by weak binding to ConA-Sepharose and strong interaction with RCA-Agarose. The presence of the polylactosamine sequence (Gal beta 1-4GlcNAc beta 1-3)n on this structure was suggested by a sialic acid independent interaction with wheat germ agglutinin (WGA)-Agarose. A sialic acid dependent WGA-interaction was observed in the ConA-unbound glycopeptides of pool A (5%). Some of the structures identified in this study may be associated with the malignant CLL phenotype and/or with a distinct stage of B cell differentiation.

Asparagine↗
PubMed2004

Yttrium and lanthanide diphosphanylamides: syntheses and structures of complexes with one [(Ph2P)2N]- ligand in the coordination sphere.

Treatment of the recently reported potassium salt [K(thf)(n)][N(PPh(2))(2)] (n=1.25, 1.5) with anhydrous yttrium or lanthanide trichlorides in THF leads after crystallization from THF/n-pentane (1:2) to the monosubstituted diphosphanylamide complexes [LnCl(2)[(Ph(2)P)(2)N](thf)(3)] (Ln=Y, Sm, Er, Yb). The single-crystal X-ray structures of these complexes show that the metal atoms are surrounded by seven ligands in a distorted pentagonal bipyramidal arrangement, in which the chlorine atoms are located in the apical positions. The diphosphanylamide ligand is always eta(2)-coordinated through the nitrogen atom and one phosphorus atom. Further reaction of [SmCl(2)[(Ph(2)P)(2)N](thf)(3)] with K(2)C(8)H(8) or reaction of [LnI(eta(8)-C(8)H(8))(thf)(3)] with [K(thf)(n)][N(PPh(2))(2)] in THF gives the corresponding cyclooctatetraene complexes [Ln[(Ph(2)P)(2)N](eta(8)-C(8)H(8))(thf)(2)] (Ln=La, Sm). The single crystals of these compounds contain enantiomerically pure complexes. Both compounds adopt a four-legged piano-stool conformation in the solid state. The structures of the A and the C enantiomers were established by single-crystal X-ray diffraction. The more soluble bistrimethylsilyl cyclooctatetraene complex [Y[(Ph(2)P)(2)N](eta(8)-1,4-(Me(3)Si)(2)C(8)H(6))(thf)(2)] was obtained by transmetallation of Li(2)[1,4-(Me(3)Si)(2)C(8)H(6)] with anhydrous yttrium trichloride in THF followed by the addition of one equivalent of [K(thf)(n)][N(PPh(2))(2)]. The (89)Y NMR signal of the complex is split up into a triplet, supporting other observations that the phosphorus atoms are chemically equivalent in solution and, thus, dynamic behavior of the ligand in solution can be anticipated.

Journal Article↗
PubMed1999

[The synaptonemal complex: a structure necessary for pairing, recombination or organization of the meiotic chromosome?].

The synaptonemal complex (SC) is a prominent and evolutionaly well conserved structure which is strictly meiotic. Several evidences from mutant phenotypes support the hypothesis that recombination and SC formation are mutually interdependent processes. Moreover, the SC recombination nodules correspond in number and location to the crossing-over events. However, recent data confirm that SC formation does not require initiation of recombination, and several observations indicate that full synapsis is not required for recombination. The potential roles played by the SC will be discussed in the following framework: First, although not required for homology recognition, the SC could promote interhomolog interactions in situations where the normal processes have failed (interlocking, heterologous pairing, etc.); Second, polymerization of the SC components might permit the recombination process to progress by modulating the number and localisation of reciprocal versus nonreciprocal exchanges (i.e. interference) and; Third, the SC may play an important role in meiotic chromosome structure and especially in inter-sister interactions.

Animals↗
PubMed2005

Uncovering the overlapping community structure of complex networks in nature and society.

Many complex systems in nature and society can be described in terms of networks capturing the intricate web of connections among the units they are made of. A key question is how to interpret the global organization of such networks as the coexistence of their structural subunits (communities) associated with more highly interconnected parts. Identifying these a priori unknown building blocks (such as functionally related proteins, industrial sectors and groups of people) is crucial to the understanding of the structural and functional properties of networks. The existing deterministic methods used for large networks find separated communities, whereas most of the actual networks are made of highly overlapping cohesive groups of nodes. Here we introduce an approach to analysing the main statistical features of the interwoven sets of overlapping communities that makes a step towards uncovering the modular structure of complex systems. After defining a set of new characteristic quantities for the statistics of communities, we apply an efficient technique for exploring overlapping communities on a large scale. We find that overlaps are significant, and the distributions we introduce reveal universal features of networks. Our studies of collaboration, word-association and protein interaction graphs show that the web of communities has non-trivial correlations and specific scaling properties.

Community Networks↗
PubMed1998

Recognition of single-stranded DNA by nuclease P1: high resolution crystal structures of complexes with substrate analogs.

The reaction mechanism of nuclease P1 from Penicillium citrinum has been investigated using single-stranded dithiophosphorylated di-, tetra-, and hexanucleotides as substrate analogs. The complexes crystallize in tetragonal and orthorhombic space groups and have been solved by molecular replacement. The high resolution structures give a clear picture of base recognition by P1 nuclease at its two nucleotide-binding sites, especially the 1.8 A structure of a P1-tetranucleotide complex which can be considered a P1-product complex. The observed binding modes are in agreement with a catalytic mechanism where the two closely spaced zinc ions activate the attacking water while the third, more exposed zinc ion stabilizes the leaving 03' oxyanion. Stacking as well as hydrogen bonding interactions with the base 5' to the cleaved phosphodiester bond are important elements of substrate binding and recognition. Modelling of a productive P1-substrate complex based on the solved structures suggests steric hindrance as the likely reason for the resistance of Rp-phosphorothioates and phosphorodithioates. Differences with the highly homologous nuclease S1 from Aspergillus oryzae are discussed.

Catalysis↗
PubMed1997

Major domain swiveling revealed by the crystal structures of complexes of E. coli Rep helicase bound to single-stranded DNA and ADP.

Crystal structures of binary and ternary complexes of the E. coli Rep helicase bound to single-stranded (ss) DNA or ssDNA and ADP were determined to a resolution of 3.0 A and 3.2 A, respectively. The asymmetric unit in the crystals contains two Rep monomers differing from each other by a large reorientation of one of the domains, corresponding to a swiveling of 130 degrees about a hinge region. Such domain movements are sufficiently large to suggest that these may be coupled to translocation of the Rep dimer along DNA. The ssDNA binding site involves the helicase motifs Ia, III, and V, whereas the ADP binding site involves helicase motifs I and IV. Residues in motifs II and VI may function to transduce the allosteric effects of nucleotides on DNA binding. These structures represent the first view of a DNA helicase bound to DNA.

Adenosine Diphosphate↗
PubMed1999

Structure-based design of Taq DNA polymerases with improved properties of dideoxynucleotide incorporation.

The Taq DNA polymerase is the most commonly used enzyme in DNA sequencing. However, all versions of Taq polymerase are deficient in two respects: (i) these enzymes incorporate each of the four dideoxynucleoside 5' triphosphates (ddNTPs) at widely different rates during sequencing (ddGTP, for example, is incorporated 10 times faster than the other three ddNTPs), and (ii) these enzymes show uneven band-intensity or peak-height patterns in radio-labeled or dye-labeled DNA sequence profiles, respectively. We have determined the crystal structures of all four ddNTP-trapped closed ternary complexes of the large fragment of the Taq DNA polymerase (Klentaq1). The ddGTP-trapped complex structure differs from the other three ternary complex structures by a large shift in the position of the side chain of residue 660 in the O helix, resulting in additional hydrogen bonds being formed between the guanidinium group of this residue and the base of ddGTP. When Arg-660 is mutated to Asp, Ser, Phe, Tyr, or Leu, the enzyme has a marked and selective reduction in ddGTP incorporation rate. As a result, the G track generated during DNA sequencing by these Taq polymerase variants does not terminate prematurely, and higher molecular-mass G bands are detected. Another property of these Taq polymerase variants is that the sequencing patterns produced by these enzymes are remarkably even in band-intensity and peak-height distribution, thus resulting in a significant improvement in the accuracy of DNA sequencing.

Crystallography, X-Ray↗