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PubMed1998

Crystal structure of the yeast MATalpha2/MCM1/DNA ternary complex.

The structure of a complex containing the homeodomain repressor protein MATalpha2 and the MADS-box transcription factor MCM1 bound to DNA has been determined by X-ray crystallography at 2.25 A resolution. It reveals the protein-protein interactions responsible for cooperative binding of MATalpha2 and MCM1 to DNA. The otherwise flexible amino-terminal extension of the MATalpha2 homeodomain forms a beta-hairpin that grips the MCM1 surface through parallel beta-strand hydrogen bonds and close-packed, predominantly hydrophobic, side chains. DNA bending induced by MCM1 brings the two proteins closer together, facilitating their interaction. An unusual feature of the complex is that an eight-amino-acid sequence adopts an alpha-helical conformation in one of two copies of the MATalpha2 monomer and a beta-strand conformation in the other. This 'chameleon' sequence of MATalpha2 may be important for recognizing natural operator sites.

Binding Sites↗
PubMed1987

Structural aspects of mammalian DNA replication: topoisomerase II.

The dynamic biology of mammalian DNA requires structural complexity. Previous studies on the structure and function of mammalian DNA have suggested that mammalian cell nuclei contain DNA organized into loop-domains by a nuclear structural subcomponent termed the nuclear matrix. The loop-domains, functioning as replicons during DNA synthesis, appear to be replicated by biosynthetic complexes located at fixed sites within the nuclear matrix milieu. Recently, we have found the mammalian DNA topoisomerase II enzyme to be associated with newly replicated DNA, and we speculate that the enzyme may be strategically positioned to untangle topologically intertwined daughter loop-domains before mitotic segregation. Further studies demonstrating growth-related elevations of DNA topoisomerase II levels in rat prostatic adenocarcinoma tissues support a role for the enzyme in cellular proliferation in vivo. The possible participation of DNA topoisomerase II in mammalian DNA replication and the proliferation-dependent appearance of the enzyme in neoplastic tissues may have important implications for therapeutic strategies directed at DNA topoisomerase II.

Animals↗
PubMed2006

Effect of constrained donor atom orientations on the stabilities, complexation kinetics, redox potentials, and structures of macrocyclic polythiaether Complexes. Copper(II) complexes with cyclopentanediyl derivatives of [14]aneS4 in 80% methanol.

The two ethylene bridges in the macrocyclic tetrathiaether 1,4,8,11-tetrathiacyclotetradecane ([14]aneS(4)) have been systematically replaced by cis- or trans-1,2-cyclopentane to generate a series of new ligands that exhibit differing preferences for the orientation of the sulfur donor atoms while maintaining constant inductive effects. The resulting five dicyclopentanediyl derivatives, along with two previously synthesized monocyclopentanediyl analogues, have been complexed with Cu(II), and their stability constants, formation and dissociation rate constants, and redox potentials have been determined in 80% methanol/20% water (by weight). The crystal structures of the Cu(II) complexes with the five dicyclopentanediyl-[14]aneS(4) diastereomers as well as the structures for a representative Cu(I) complex and one of the free ligands have also been determined. The properties of these complexes are compared to previous data obtained for the corresponding cyclohexanediyl derivatives in an attempt to shed additional light on the influence of sterically constraining substituents upon the properties of macrocyclic ligand complexes.

Journal Article↗
PubMed2003

Ambiguity in the brain: what brain imaging reveals about the processing of syntactically ambiguous sentences.

Two fMRI studies investigated the time course and amplitude of brain activity in language-related areas during the processing of syntactically ambiguous sentences. In Experiment 1, higher levels of activation were found during the reading of unpreferred syntactic structures as well as more complex structures. In Experiments 2A and 2B higher levels of brain activation were found for ambiguous sentences compared with unambiguous sentences matched for syntactic complexity, even when the ambiguities were resolved in favor of the preferred syntactic construction (despite the absence of this difference in previous reading time results). Although results can be reconciled with either serial or parallel models of sentence parsing, they arguably fit better into the parallel framework. Serial models can admittedly be made consistent but only by including a parallel component. The fMRI data indicate the involvement of a parallel component in syntactic parsing that might be either a selection mechanism or a construction of multiple parses.

Adult↗
PubMed1995

Crystal structures of factor Xa specific inhibitors in complex with trypsin: structural grounds for inhibition of factor Xa and selectivity against thrombin.

Crystal structures of DX9065a and a related bisamidino-aryl inhibitor specific for the blood-clotting factor Xa have been solved in complex with bovine beta-trypsin to a resolution of 1.9 A. Each inhibitor exhibits an extended conformation along the active site, in contrast to the compact folded structures observed for thrombin specific inhibitors. Few direct contacts (predominantly in the S1 pocket) are made between trypsin and the inhibitors. Transfer of the inhibitors to the active site of factor Xa suggests a three-site interaction: salt bridge formation at the base of the primary specificity pocket, extensive hydrophobic surface burial and a weak electrostatic interaction between the distal basic component of the inhibitor and an electronegative cavity of factor Xa formed by three backbone carbonyl oxygens. Additivity of these three interactions is the basis for the observed strong inhibition of factor Xa and provides a framework for the design of novel factor Xa inhibitors. A propionic acid group of the inhibitor would clash with the thrombin specific '60-insertion loop', thus conferring selectivity against thrombin.

Amino Acid Sequence↗
PubMed2006

CO2 Fixation by Cu2+ and Zn2+ complexes of a terpyridinophane aza receptor. Crystal structures of Cu2+ complexes, pH-metric, spectroscopic, and electrochemical studies.

The synthesis of the terpyridinophane-type polyamine 2,6,9,12,16-pentaaza[17]-(5,5' ')-cyclo-(2,2':6',2' ')-terpyridinophane heptahydrobromide tetrahydrate (L.7HBr.4H2O) is described. L presents six protonation constants with values in the range 9.21-3.27 logarithmic units. L interacts with Cu2+ and Zn2+ forming in both cases, neutral, protonated, and hydroxylated mono- and binuclear complexes whose constants have been calculated by potentiometry in 0.15 M NaClO4 at 298.1 K. The crystal structures of the compounds [Cu(HL-carb)(H2O)](ClO4)3.2H2O (1) and [Cu2(H2L)(CO3)]2(ClO4)8.9H2O (2) have been solved by X-ray diffraction. In 1, the metal center presents square pyramidal geometry. The base of the pyramid is formed by the three nitrogen atoms of pyridine and one oxygen atom of a CO2 group which is forming a carbamate bond with the central nitrogen atom of the polyamine chain. The axial position is occupied by a water molecule. In 2, one Cu2+ is bound by the three pyridine nitrogens and the other one by the three central nitrogen atoms of the polyamine chain. The square planar coordination geometry is completed by a carbonate group taken up from the atmosphere that behaves as a bridging mu,mu'-ligand between the two centers. The pH-metric titrations on the ternary Cu2+-L-carbonate and Zn2+-L-carbonate systems show the extensive formation of adduct species which above pH 6 are formed quantitatively in solution. The stoichiometries of the main species formed in solution at pH = 6.8 agree with those found in the crystalline compounds. CO2 uptake by the Zn2+ and Cu2+ 1:1 complexes in aqueous solution has also been followed by recording the variations in the band at ca. 300 nm. The formation of the Zn2+ carbamate moiety has been evidenced by 13C NMR and ESI spectroscopy.

Carbon Dioxide↗
PubMed2005

Linear recursive distributed representations.

Connectionist networks have been criticized for their inability to represent complex structures with systematicity. That is, while they can be trained to represent and manipulate complex objects made of several constituents, they generally fail to generalize to novel combinations of the same constituents. This paper presents a modification of Pollack's Recursive Auto-Associative Memory (RAAM), that addresses this criticism. The network uses linear units and is trained with Oja's rule, in which it generalizes PCA to tree-structured data. Learned representations may be linearly combined, in order to represent new complex structures. This results in unprecedented generalization capabilities. Capacity is orders of magnitude higher than that of a RAAM trained with back-propagation. Moreover, regularities of the training set are preserved in the new formed objects. The formation of new structures displays developmental effects similar to those observed in children when learning to generalize about the argument structure of verbs.

Algorithms↗
PubMed1988

[Action of khanerol on the superhelical DNA structure of S-37 cells].

The damaging effects on the structure of a supramolecular DNA complex of sarcoma-37 cells in mice following the use of the therapeutic doses of khanerol were found. Capillary elastoviscosimetry and nucleoid sedimentation procedure showed that the damage of the supramolecular DNA complex structure becomes apparent already after 4 hours, and increases by 24 hour. In studies of the binding of khanerol with DNA by Cd and Tmelt. the procedure showed direct interaction of khanerol with DNA. The role of conformational changes of the supramolecular DNA complex in the cytotoxic action of antitumour agents is discussed.

Animals↗
PubMed2003

Oxidation and metal-ion affinities of a novel cyclic tetrasaccharide.

The cyclic tetrasaccharide, cyclo-(-->6)-alpha-D-Glcp-(1-->3)-alpha-D-Glcp-(1-->6)-alpha-D-Glcp-(1-->3)-alpha-D-Glcp-(1-->), was oxidized in high yield to a dicarboxylic acid, cyclo-(-->6)-alpha-D-Glcp-(1-->3)-alpha-D-GlcpA-(1-->6)-alpha-D-Glcp-(1-->3)-alpha-D-GlcpA-(1-->). The parent and oxidized compound were then screened for the ability to form stable complexes with 20 metal cations. Ion-exchange thin-layer chromatography was utilized to survey binding in aqueous and 50% methanolic solutions. The screening identified Pb2+, Fe2+ and Fe3+ as forming strong metal chelates with the oxidized cyclic tetrasaccharide. The stoichiometry of the oxidized cyclic tetrasaccharide and Pb2+ complex was determined to be 1:1 using aqueous gel-permeation chromatography. Perturbations between the free and complexed structure were examined using NMR spectroscopy. Molecular simulations were used to identify a probable structure of oxidized cyclic tetrasaccharide complexed with Pb2+.

Catalysis↗
PubMed2005

A comparison of staphostatin B with standard mechanism serine protease inhibitors.

Staphostatins are the endogenous, highly specific inhibitors of staphopains, the major secreted cysteine proteases from Staphylococcus aureus. We have previously shown that staphostatins A and B are competitive, active site-directed inhibitors that span the active site clefts of their target proteases in the same orientation as substrates. We now report the crystal structure of staphostatin B in complex with wild-type staphopain B at 1.9 A resolution. In the complex structure, the catalytic residues are found in exactly the positions that would be expected for uncomplexed papain-type proteases. There is robust, continuous density for the staphostatin B binding loop and no indication for cleavage of the peptide bond that comes closest to the active site cysteine of staphopain B. The carbonyl carbon atom C of this peptide bond is 4.1 A away from the active site cysteine sulfur Sgamma atom. The carbonyl oxygen atom O of this peptide bond points away from the putative oxyanion hole and lies almost on a line from the Sgamma atom to the C atom. The arrangement is strikingly similar to the "ionmolecule" arrangement for the complex of papain-type enzymes with their substrates but differs significantly from the arrangement conventionally assumed for the Michaelis complex of papain-type enzymes with their substrates and also from the arrangement that is crystallographically observed for complexes of standard mechanism inhibitors and their target serine proteases.

Bacterial Proteins↗
PubMedDate not supplied

[Spatial structure of DNA complex with the oligopeptide dansyl hydrazide trivaline].

The structure of complexes between double-stranded DNA and oligopeptide dansyl hydrazide trivaline was studied by linear dichroism, electron microscopy and hydrodynamical methods. The results show that the binding of the oligopeptide to DNA is a cooperative process that leads to the formation of particles significantly differing in the structure from free DNA. The linear dichroism studies were carried out in a wide range of flow-speed gradients. From the theoretical analysis of these data a conclusion can be drawn that the DNA-oligopeptide complexes possesses a higher rigidity as compared with that of free DNA. The hydrodynamical behaviour of these particles is consistent with the rigid rod-like structure of the particles with a long axis nearly parallel to the DNA helix axis in the complexes. The sedimentation patterns of the complexes suggest the existence of the fast and slow sedimenting species. The sedimentation coefficient measured for a fast sedimenting species is about 3 times higher than that of free DNA. The linear dichroism spectra obtained for the floworiented DNA-oligopeptide complexes correlate with the existence of a superhelical organization of DNA in the complex. This offers a possibility for the determining of the angle of the DNA local axis inclination with respect to the superhelix axis. On electron micrographs the DNA-oligopeptide complexes look like rod-shaped structures with the thickness of about 180 A and 80 A on the rotatory-shadowed preparations and on the uranylacetate stained preparations, respectively. The rod-shaped structures are formed by two interwound DNA molecules. The superhelix has a pitch of about 150 A with an angle of twist inclination of about 40 degrees. These values are in good agreement with the optical anisotropic data. It is suggested that the complex structure is stabilized by periodically spaced hydrophobic contacts between the dimeric oligopeptide species bound to the DNA molecules.

DNA↗
PubMed1999

NMR structure of phospho-tyrosine signaling complexes.

A structural basis for activation and substrate specificity of src tyrosine kinases, and regulation of protein-protein association by tyrosine phosphorylation is described. Lyn, a src-family tyrosine kinase, recognizes and phosphorylates the immunoreceptor tyrosine-based activation motif, ITAM, a critical component in transmembrane signal transduction in hemopoietic cells. The structure of an ITAM peptide substrate bound to an active form of Lyn tyrosine kinase was determined by high-resolution NMR, and a model of the complex was generated using the crystallographic structure of Lck, a closely related Src-family kinase. The results provide a rationale for the conserved ITAM residues and specificity of Lyn, and suggest that substrate plays a role in stabilizing the kinase conformation optimal for catalysis. It is our hope that the Lck-ITAM peptide model complex will be useful in aiding structure-based drug design efforts that target substrate binding determinants in the design. Concerning the regulation of protein-protein association, we report on a complex between erythrocyte band 3 and two glycolytic enzymes, aldolase and glyceraldehyde-3-phosphate dehydrogenase. The formation of this complex is negatively regulated by tyrosine phosphorylation of band 3 by p72syk tyrosine kinase. In red blood cells, this association results in a decrease in glycolysis due to competitive inhibition of the glycolytic enzymes. The structure of band 3 recognized by the glycolytic enzymes was determined by solution NMR, and found to be a loop structure with tyrosine centrally positioned and excluded from intermolecular contact. This phosphorylation sensitive interaction, or PSI, loop may be the basis of a general mechanism for negative regulation through tyrosine phosphorylation.

Drug Design↗
PubMed1986

A new approach toward a pancreas-seeking zinc radiopharmaceutical. I. Accumulation of 65Zn-amino acid and aminopolycarboxylic acid complexes in pancreatic tissue slices.

There have been many attempts to develop zinc-containing radiopharmaceuticals for use as pancreas-seeking agents, but little consideration has been given to Zn-complex structure as being a factor that contributes to Zn utilization by the pancreas. In the present study, various ligands having N-O donor groups (amino acids and aminopolycarboxylic acids) with variable numbers of coordination sites (2-6) were investigated with regard to the coordination of the radiometal Zn. As an experimental model, freshly prepared slices of rat pancreas were studied, and Sephadex-column chromatography analysis was also performed. The structure and stability of Zn complexes were found to affect the accumulation of Zn in pancreas slices. In particular, the administration of tetradentate ligand complexes of 65Zn-ethylenediamine-N,N'-diacetic acid (EDDA) and 65Zn-nitrilotriacetic acid (NTA) resulted in high Zn utilization in the pancreas. Also, Zn complexes of intermediate stability (as demonstrated by elution behavior at Sephadex-column chromatography) produced the best results.

Amino Acids↗
PubMed2004

Chemical biology of the sugar code.

A high-density coding system is essential to allow cells to communicate efficiently and swiftly through complex surface interactions. All the structural requirements for forming a wide array of signals with a system of minimal size are met by oligomers of carbohydrates. These molecules surpass amino acids and nucleotides by far in information-storing capacity and serve as ligands in biorecognition processes for the transfer of information. The results of work aiming to reveal the intricate ways in which oligosaccharide determinants of cellular glycoconjugates interact with tissue lectins and thereby trigger multifarious cellular responses (e.g. in adhesion or growth regulation) are teaching amazing lessons about the range of finely tuned activities involved. The ability of enzymes to generate an enormous diversity of biochemical signals is matched by receptor proteins (lectins), which are equally elaborate. The multiformity of lectins ensures accurate signal decoding and transmission. The exquisite refinement of both sides of the protein-carbohydrate recognition system turns the structural complexity of glycans--a demanding but essentially mastered problem for analytical chemistry--into a biochemical virtue. The emerging medical importance of protein-carbohydrate recognition, for example in combating infection and the spread of tumors or in targeting drugs, also explains why this interaction system is no longer below industrial radarscopes. Our review sketches the concept of the sugar code, with a solid description of the historical background. We also place emphasis on a distinctive feature of the code, that is, the potential of a carbohydrate ligand to adopt various defined shapes, each with its own particular ligand properties (differential conformer selection). Proper consideration of the structure and shape of the ligand enables us to envision the chemical design of potent binding partners for a target (in lectin-mediated drug delivery) or ways to block lectins of medical importance (in infection, tumor spread, or inflammation).

Binding Sites↗
PubMed2005

Structural analysis of threonine 342 mutants of soybean beta-amylase: role of a conformational change of the inner loop in the catalytic mechanism.

Two different conformations of the inner loop (residues 340-346) have been found in the soybean beta-amylase structures. In the "product form", the Thr 342 residue creates hydrogen bonds with Glu 186 (catalytic acid) and with the glucose residues at subsites -1 and +1, whereas most of those interactions are lost in the "apo form". To elucidate the relationship between the structural states of the inner loop and the catalytic mechanism, Thr 342 was mutated to Val, Ser, and Ala, respectively, and their crystal structures complexed with maltose were determined together with that of the apo enzyme at 1.27-1.64 A resolutions. The k(cat) values of the T342V, T342S, and T342A mutants decreased by 13-, 360-, and 1700-fold, respectively, compared to that of the wild-type enzyme. Whereas the inner loops in the wild-type/maltose and T342V/maltose complexes adopted the product form, those of the T342S/maltose and T342A/maltose complexes showed the apo form. Structural analyses suggested that the side chain of Thr 342 in product form plays an important role in distorting the sugar ring at subsite -1, stabilizing the deprotonated form of Glu 186, and grasping the glucose residue of the remaining substrate at subsite +1. The third hypothesis was proved by the fact that T342V hydrolyzes maltoheptaose following only multichain attack in contrast to multiple attack of the wild-type enzyme.

Amino Acid Sequence↗
PubMed2003

Monte Carlo simulations of polyampholyte-polyelectrolyte complexes: effect of charge sequence and strength of electrostatic interactions.

We present the results of Monte Carlo simulations of complexation between polyampholyte and polyelectrolyte chains. Polymers are modeled as bead-spring chains of charged Lennard-Jones particles each consisting of 32 monomers. Formation of a polyampholyte-polyelectrolyte complex is driven by polarization-induced attractive interactions. The complex is usually formed at the end of the polyelectrolyte with the polyampholyte chain elongated and aligned along the polyelectrolyte backbone. This complex structure between the polarized polyampholyte chain and the polyelectrolyte leads to maximization of the attractive and minimization of the repulsive electrostatic interactions. The size of a polyampholyte in a complex is usually larger than that of an isolated polyampholyte chain. We also observed that initially collapsed polyampholytes undergo a coil-globule transition by forming a complex. The structure of a polyampholyte-polyelectrolyte complex was analyzed by tail and loop distribution functions. We have found that the number of loops increases while their sizes decrease with the strength of the electrostatic interactions. Polyampholytes with random charge sequence form stronger complexes with polyelectrolytes than those with alternating charge sequence. Polyampholytes with long blocky sequences form a double helix with a polyelectrolyte at sufficiently large values of the Bjerrum length.

Journal Article↗
PubMed1991

Transferrin-polycation-DNA complexes: the effect of polycations on the structure of the complex and DNA delivery to cells.

We have previously described a gene delivery system based upon the receptor-mediated endocytosis of DNA complexed with transferrin-polycation conjugates. This delivery system has been found to be very effective for both the internalization and the expression of genetic material in cells that have many transferrin receptors. Upon scrutinization of the parameters involved in this method, which we have termed transferrinfection, we note two important features of the process: the polycation in polycation-transferrin conjugates, as expected, serves to attach the transferrin moiety to the DNA and, in addition, the polycation functions to condense the DNA into a doughnut structure. Electron microscopic analysis of a range of poorly active to highly active transferrinfection samples reveals a strong correlation between DNA condensation and cellular DNA uptake. Furthermore, we demonstrate that the transfection activity of the DNA complex can be increased by addition of free polycation as long as a sufficient quantity of polycation-transferrin conjugates remains in the complex to ensure its binding to the cellular receptor.

Amino Acid Sequence↗
PubMed2006

Amplitudes and directions of internal protein motions from a JAM analysis of 15N relaxation data.

A method has been developed for characterizing dynamic structures of proteins in solution by using nuclear magnetic resonance (NMR) restraints and 15N relaxation data. This method is based on the concept of the jumping-among-minima (JAM) model. In this model we assume that protein dynamics can be described on the basis of conformational substates, and involves intra- and inter-substate motion. A set of substates is created by picking energy-minimized conformations from the conformational space consistent with the geometric NMR restraints. Intra-substate motions, which occur on the timescale of approximately 10 ps, are simulated with molecular dynamics (MD) calculations with force-field energy terms. Statistical weights of the conformational substates are determined to reproduce the NMR relaxation parameters. The refinement procedure consists of four stages: (i) determination of the ensemble of structures that satisfy NMR restraints, (ii) determination of intra-substate fluctuation, (iii) determination of statistical weights of conformational substates to reproduce model-free relaxation parameters, and (iv) analysis of the resulting dynamic structure to determine amplitudes and directions of internal protein motions. This method was employed to investigate structure and dynamics of the adhesion domain of human CD2 (hCD2) in solution. Two major collective modes, whose contributions to atomic mean-square fluctuations are 77.1% in total, are identified by the refinement. The first mode is interpreted as a rigid-body motion of a protein segment consisting of a part of the B--C loop, a part of the F strand, and the F--G loop. Another type of smaller-amplitude mode is indicated for the C'--C'' loop. The motions affect primarily the curvature of the slightly concave counterreceptor-binding site and represent transitions between a concave (closed) and flat (open) binding face. By comparing the ensemble of structures in solution to the complex structure with counterreceptor CD58, we found that these two types of motions resemble the change upon counterreceptor binding.

Models, Molecular↗