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PubMed1967

Crystal structure of the 1: 1 complex of 5-fluorouracil and 9-ethylhypoxanthine.

9-Ethylhypoxanthine and 5-fluorouracil form a 1 : 1 crystalline complex. The structure of this complex has been solved by x-ray diffraction analysis. The molecules crystallize in a monoclinic lattice and form a sheet structure in which pairs of fluorouracil molecules are held together by two hydrogen bonds. The 9-ethylhypoxanthine residues fill up the rest of the molecular sheet by forming single hydrogen bonds with each uracil pair.

Chemical Phenomena↗
PubMed1989

[Quantitative analysis of the bronchial tree structure in dogs and polar foxes].

Bronchial tree in the blue fox possesses a more complex structure that that of the dog and is characterized with a greater length and a greater number of generations in large and middle bronchi with a simultaneous decrease in the number of small bronchiole generations and a greater irregularity and asymmetry within segments. These peculiarities are connected with ecologically ensured in the North demands on increase of anatomically dead space.

Animals↗
PubMed2006

Interesting coordination abilities of antiulcer drug famotidine and antimicrobial activity of drug and its cobalt(III) complex.

Crystal structure of a novel cobalt(III) complex with antiulcer drug famotidine and ethylenediamine was determined. This is the second structure of a transition metal complex with famotidine resolved by a single crystal X-ray analysis, in which famotidine shows different mode of coordination than that observed in the other cases. Drug molecule is coordinated to metal ion as a tetradentate ligand through guanidine N6, thiazole N4, thioether S2 and terminal N3 atom. Two NH(2) groups (N3H(2) and N6H(2)) are deprotonated and drug coordinates as dianion. In the asymmetric unit, one chloride anion and one water molecule were found to complete the complex stoichiometry. The structure of the complex is abundant in atoms, which can be involved in hydrogen bond formation either as hydrogen acceptors or hydrogen donors. Because of that, a great number of hydrogen bonds dominates the crystal packing. Beside the hydrogen bonds, there are two interesting noncovalent interactions: CH(...)pi and NH(...)pi within the famotidine anion, which stabilize the complex structure. The pi(...)pi stacking interactions between neighboring complex cations are also observed. Antibacterial and antifungal activity of famotidine and its newly synthesized complex against representative bacteria: Escherichia coli, Staphilococcus aureus and Micrococcus lysodeikticus and fungi: Aspergillus niger and Candida albicans were examined. The results indicate a higher selectivity of the famotidine-Co(III) complex, as well as better growth inhibitory activity (lower MIC values (MIC, minimal inhibitory concentration)) in comparison with the drug alone.

Anti-Bacterial Agents↗
PubMed2006

Statistical deconvolution of enthalpic energetic contributions to MHC-peptide binding affinity.

BACKGROUND: MHC Class I molecules present antigenic peptides to cytotoxic T cells, which forms an integral part of the adaptive immune response. Peptides are bound within a groove formed by the MHC heavy chain. Previous approaches to MHC Class I-peptide binding prediction have largely concentrated on the peptide anchor residues located at the P2 and C-terminus positions. RESULTS: A large dataset comprising MHC-peptide structural complexes was created by re-modelling pre-determined x-ray crystallographic structures. Static energetic analysis, following energy minimisation, was performed on the dataset in order to characterise interactions between bound peptides and the MHC Class I molecule, partitioning the interactions within the groove into van der Waals, electrostatic and total non-bonded energy contributions. CONCLUSION: The QSAR techniques of Genetic Function Approximation (GFA) and Genetic Partial Least Squares (G/PLS) algorithms were used to identify key interactions between the two molecules by comparing the calculated energy values with experimentally-determined BL50 data. Although the peptide termini binding interactions help ensure the stability of the MHC Class I-peptide complex, the central region of the peptide is also important in defining the specificity of the interaction. As thermodynamic studies indicate that peptide association and dissociation may be driven entropically, it may be necessary to incorporate entropic contributions into future calculations.

Binding Sites↗
PubMed1987

Three-dimensional structure of the complex flagellar filament of Rhizobium lupini and its relation to the structure of the plain filament.

Electron micrographs of negatively stained preparations were used to obtain a three-dimensional reconstruction of the complex flagellar filament of Rhizobium lupini H13-3. The complex filament has an organization similar to that of the more common plain filament, but the subunits are perturbed in a pairwise fashion to generate a very distinctive set of three continuous ridges of density along the outer surface of the filament. In the three-dimensional map, the design of the complex filament is similar to that of the plain filament described in the accompanying paper. The structures consist of 11 segmented rods of density lying at a radius of 65 to 70 A. The exterior surfaces of both kinds of filaments consist of features that protrude from the segmented rods. The interiors of both consist of arms that extend inwards from the rods. In the case of the complex filament, but not of the plain filament, the inner arms interact to generate three tubular features, which, together with the three outer ridges, may account for the more brittle and, by implication, stiffer nature of the complex filament.

Computer Simulation↗
PubMed2004

Loop relaxation, a mechanism that explains the reduced specificity of rabbit 20alpha-hydroxysteroid dehydrogenase, a member of the aldo-keto reductase superfamily.

The aldo-keto reductase rabbit 20alpha-hydroxysteroid dehydrogenase (rb20alpha-HSD; AKR1C5) is less selective than other HSDs, since it exerts its activity both on androgens (C19 steroids) and progestins (C21 steroids). In order to identify the molecular determinants responsible for this reduced selectivity, binary (NADPH) and ternary (NADP(+)/testosterone) complex structures were solved to 1.32A and 2.08A resolution, respectively. Inspection of the cofactor-binding cavity led to the identification of a new interaction between side-chains of residues His222 and Lys270, which cover the central phosphate chain of the cofactor, reminiscent of the "safety-belt" found in other aldo-keto reductases. Testosterone is stabilized by a phenol/benzene tunnel composed of side-chains of numerous residues, among which Phe54, which forces the steroid to take up an orientation markedly contrasting with that found in HSD ternary complexes reported. Combining structural, site-directed mutagenesis, kinetic and fluorescence titration studies, we found that the selectivity of rb20alpha-HSD is mediated by (i) the relaxation of loop B (residues 223-230), partly controlled by the nature of residue 230, (ii) the nature of the residue found at position 54, and (iii) the residues found in the C-terminal tail of the protein especially the side-chain of the amino acid 306.

20-alpha-Hydroxysteroid Dehydrogenase↗
PubMed2005

Oxidative stress-dependent structural and functional switching of a human 2-Cys peroxiredoxin isotype II that enhances HeLa cell resistance to H2O2-induced cell death.

Although biochemical properties of 2-Cys peroxiredoxins (Prxs) have been extensively studied, their real physiological functions in higher eukaryotic cells remain obscure and certainly warrant further study. Here we demonstrated that human (h) PrxII, a cytosolic isotype of human 2-Cys Prx, has dual functions as a peroxidase and a molecular chaperone, and that these different functions are closely associated with its adoption of distinct protein structures. Upon exposure to oxidative stress, hPrxII assumes a high molecular weight complex structure that has a highly efficient chaperone function. However, the subsequent removal of stressors induces the dissociation of this protein structure into low molecular weight proteins and triggers a chaperone-to-peroxidase functional switch. The formation of a high molecular weight hPrxII complex depends on the hyperoxidation of its N-terminal peroxidatic Cys residue as well as on its C-terminal domain, which contains a "YF motif" that is exclusively found in eukaryotic 2-Cys Prxs. A C-terminally truncated hPrxII exists as low and oligomeric protein species and does not respond to oxidative stress. Moreover, this C-terminal deletion of hPrxII converted it from an oxidation-sensitive to a hyperoxidation-resistant form of peroxidase. When functioning as a chaperone, hPrxII protects HeLa cells from H(2)O(2)-induced cell death, as measured by a terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay and fluorescence-activated cell sorting analysis.

Cell Death↗
PubMed1987

S4-alpha mRNA translation regulation complex. II. Secondary structures of the RNA regulatory site in the presence and absence of S4.

The secondary structure of the Escherichia coli alpha mRNA leader sequence has been determined using nucleases specific for single- or double-stranded RNA. Three different length alpha RNA fragments were studied at 0 degrees C and 37 degrees C. A very stable eight base-pair helix forms upstream from the ribosome initiation site, defining a 29 base loop. There is evidence for base-pairing between nucleotides within this loop and for a "pseudo-knot" interaction of some loop bases with nucleotides just 3' to the initiation codon, forming a region of complex structure. A weak helix also pairs sequences near the 5' terminus of the alpha mRNA with bases near the Shine-Dalgarno sequence. Affinity constants for the translational repressor S4 binding different length alpha mRNA fragments indicate that most of the S4 recognition features must be contained within the main helix and hairpin regions. Binding of S4 to the alpha mRNA alters the structure of the 29 base hairpin region, and probably melts the weak pairing between the 5' and 3' termini of the leader. The pseudo-knot structure and the conformational changes associated with it provide a link between the structures of the S4 binding site and the ribosome binding site. The alpha mRNA may therefore play an active role in mediating translational repression.

Autoradiography↗
PubMed2001

Computational analysis of PKA-balanol interactions.

Protein kinases are important targets for designing therapeutic drugs. This paper illustrates a computational approach to extend the usefulness of a single protein-inhibitor structure in aiding the design of protein kinase inhibitors. Using the complex structure of the catalytic subunit of PKA (cPKA) and balanol as a guide, we have analyzed and compared the distribution of amino acid types near the protein-ligand interface for nearly 400 kinases. This analysis has identified a number of sites that are more variable in amino acid types among the kinases analyzed, and these are useful sites to consider in designing specific protein kinase inhibitors. On the other hand, we have found kinases whose protein-ligand interfaces are similar to that of the cPKA-balanol complex and balanol can be a useful lead compound for developing effective inhibitors for these kinases. Generally, this approach can help us discover new drug targets for an existing class of compounds that have already been well characterized pharmacologically. The relative significance of the charge/polarity of residues at the protein-ligand interface has been quantified by carrying out computational sensitivity analysis in which the charge/polarity of an atom or functional group was turned off/on, and the resulting effects on binding affinity have been examined. The binding affinity was estimated by using an implicit-solvent model in which the electrostatic contributions were obtained by solving the Poisson equation and the hydrophobic effects were accounted for by using surface-area dependent terms. The same sensitivity analysis approach was applied to the ligand balanol to develop a pharmacophoric model for searching new drug leads from small-molecule libraries. To help evaluate the binding affinity of designed inhibitors before they are made, we have developed a semiempirical approach to improve the predictive reliability of the implicit-solvent binding model.

Azepines↗
PubMed2006

[The life of human hair follicle revealed].

The human hair follicle is a unique appendage which results from epithelio-mesenchymal interactions initiated around the 3rd month of development. This appendage has a very complex structure, with a dermal compartment and an epithelial compartment. The dermal compartment comprises the connective tissue sheath and the dermal papilla, both of which are irrigated by microvessels. The epithelial compartment is made of highly replicating matrix cells giving rise to three concentrical domains, namely the outer root sheath, the inner root sheath and the hair shaft. The pigmentation unit, responsible for hair color, is made of fully active melanocytes located on top of the dermal papilla. Altogether a hair follicle contains more than 20 different cell types, engaged in different differentiation pathways and/or interacting with each other. This complex appendage has a unique behavior in mammals since, after a hair production phase, it involutes in place before entering a resting phase after which it renews itself under a cyclical but stochastic way, out of a double reservoir of pluripotent stem cells able to also regenerate epidermis. For yet unknown reasons, this well ordered process can be disturbed, provoking alopecia. The pigmentation unit also renews itself under a cyclical way, out of a melanocyte progenitor reservoir which progressively declines with time, provoking the hair whitening process. Finally, the shape of the hair shaft is programmed from the bulb. What makes this appendage unique and fascinating is its high degree of autonomy, its incredibly complex though stable structure, the number of different cell types interacting under an equilibrated way and its potential of regeneration. It represents a true paradigm of tissue homeostasis, exemplifying in a small living cylinder all the fundamental laws of cell-cell and tissue interactions. This life is revealed in this short synthesis.

Growth Substances↗
PubMed1982

Oligosaccharide branching of glycoproteins: biosynthetic mechanisms and possible biological functions.

One of the most striking features of N- and O-glycosyl oligosaccharides and of lipid-linked oligosaccharides is the high degree of branching of these complex structures. Both proteins and nucleic acids are essentially linear structures and are synthesized by template mechanisms. The branched nature of complex carbohydrates dictates a totally different mechanism of biosynthetic control. Although there are undoubtedly many factors controlling this assembly (e.g. subcellular compartmentation, availability of substrates, cations), our laboratory has studied primarily the enzymatic factors that control the assembly of branched N-glycosyl (Asn-GlcNAc type) and O-glycosyl (Ser[Thr]-GalNAc type) oligosaccharides. There are three basic types of control points that appear to direct biosynthesis. (a) There may be two or more enzymes capable of acting on a single common substrate. Control at this juncture is exerted by the relative activities of these enzymes in a particular tissue. (b) Addition of a specific sugar to the growing oligosaccharide may shut off one or more subsequent enzyme steps, thereby 'freezing' the structure at a certain stage in its synthesis. (c) Progression of the pathway may be impossible until a certain key sugar residue is inserted into the growing oligosaccharide chain. Examples of all three types of control occur in the assembly of both N- and O-glycosyl oligosaccharides. This paper discusses our work on the N-acetylglucosaminyltransferases, which initiate branches in N-glycosyl oligosaccharides, as well as some studies on glycosyltransferases that control the assembly of the four basic Ser(Thr)-GalNAc cores. Important features at all stages of control are the three-dimensional shape of the oligosaccharide, the effect of certain key sugar residues on this three-dimensional shape and the stereochemistry of the interaction of oligosaccharides with proteins. From a functional point of view, protein-oligosaccharide interaction is of vital importance not only to enzyme control mechanisms but to a variety of biological problems such as malignancy and cell-cell interactions, differentiation and development, and susceptibility of cells to hormones, drugs and toxins.

Animals↗
PubMed1993

Dynamic aspects of microfilament-membrane attachments.

Microfilament-membrane attachment sites are complex structures that are essential for tissue differentiation in animals. In this article, we focus on the assembly and dynamics of such contact sites as seen in two cell types differentiating in cultures of the embryonic chicken heart, cardiocytes and fibroblasts. Concentrating on the cytoplasmic domain, we refer to previous biochemical, light, and electron microscopic studies on the structure and dynamics of these regions and supplement them with our own recent data. Although many details are still to be elucidated, we would like to propose the following model. Actin, alpha-actinin and vinculin are the major structural components of all microfilament-membrane contacts. Various subtypes of junctions are characterised by additional structural components or by specific isoforms. Temporal regulation of contact sites is linked to assembly and disassembly of microfilaments and might be controlled by special regulatory proteins. Finally, the cytoplasmic domains of junctional complexes may serve as structural matrices for the positioning of proteins involved in signal transduction pathways.

Actin Cytoskeleton↗
PubMed2000

The wide binding properties of a wheat nonspecific lipid transfer protein. Solution structure of a complex with prostaglandin B2.

The 3D solution structure of wheat nonspecific lipid transfer protein (ns-LTP) complexed with prostaglandin B2, a lipid with both vinyl and hydroxylated groups, has been determined by 1H 2D NMR. The global fold of the protein is close to the previously published structures of wheat, maize, barley and rice ns-LTPs. The ligand is almost completely embedded in the hydrophobic core of the protein. Structure comparisons of free and bound wheat ns-LTP reveal that the binding of prostaglandin B2 hardly affects the global fold of the protein. The structural data on this unusual complex are discussed and compared with other known ns-LTP lipid-complexes.

Binding Sites↗
PubMed1999

Native-state hydrogen-exchange studies of a fragment complex can provide structural information about the isolated fragments.

Ordered protein complexes are often formed from partially ordered fragments that are difficult to structurally characterize by conventional NMR and crystallographic techniques. We show that concentration-dependent hydrogen exchange studies of a fragment complex can provide structural information about the solution structures of the isolated fragments. This general methodology can be applied to any bimolecular or multimeric system. The experimental system used here consists of Ribonuclease S, a complex of two fragments of Ribonuclease A. Ribonuclease S and Ribonuclease A have identical three-dimensional structures but exhibit significant differences in their dynamics and stability. We show that the apparent large dynamic differences between Ribonuclease A and Ribonuclease S are caused by small amounts of free fragments in equilibrium with the folded complex, and that amide exchange rates in Ribonuclease S can be used to determine corresponding rates in the isolated fragments. The studies suggest that folded RNase A and the RNase S complex exhibit very similar dynamic behavior. Thus cleavage of a protein chain at a single site need not be accompanied by a large increase in flexibility of the complex relative to that of the uncleaved protein.

Amino Acid Sequence↗
PubMed2000

CH/pi interactions in the crystal structure of TATA-box binding protein/DNA complexes.

Crystal structures of TATA box-binding proteins (TBP) of various sources bound to their promoter DNA (TATA box) were analyzed with use of our program CHPI. A number of short CH/Csp2 contacts have been unveiled in these complexes at the boundary of TBP and the TATA box minor groove. The result was discussed in the context of the CH/pi interaction. Thus, the nature of nonpolar forces, reported in the past at the interface of the two components, has been attributed to the CH/pi interaction. Furthermore, many CH/pi contacts have been disclosed within the same strand of the promoter DNA. The structure of the TATA element, partially unwound and severely bent on complexation, seems to be stabilized by CH/pi interactions; H2' of the deoxyribose moiety and the methyl group in the thymine nucleotide play the primary role.

Binding Sites↗
PubMed2001

Interaction between peroxisome proliferator-activated receptor gamma and its agonists: docking study of oximes having 5-benzyl-2,4-thiazolidinedione.

The molecular modelling of oximes having 5-benzyl-2,4-thiazolidinedione moieties, agonists of the peroxisome proliferator-activated receptor gamma (PPAR gamma), was performed with respect to their structures complexed with the ligand binding domain of PPAR gamma. For each ligand molecule, the 5-benzyl-2,4-thiazolidinedione head group was used as an anchor and the conformation of the rest of the molecule was searched for the most energetically favorable interaction with the receptor by systematic conformation search and manual modelling. Although both tail-up and tail-down configurations, which have been observed in the crystal structure of eicosapentaenoic acid when complexed with PPAR delta, appeared among the lowest energy structures for most of the compounds, potent agonists were found to adopt a configuration similar to that of rosiglitazone when bound to PPAR gamma, according to the crystal structure. The structure-activity relationships were analyzed based on the receptor-ligand interaction. The alkyl group and the aromatic ring of the tail group of the ligands had hydrophobic interactions with the receptor, and these interactions were found to be essential for the strong activity.

Hypoglycemic Agents↗
PubMed1999

Crystal structures of thrombin complexed to a novel series of synthetic inhibitors containing a 5,5-trans-lactone template.

The binding modes of four active site-directed, acylating inhibitors of human alpha-thrombin have been determined using X-ray crystallography. These inhibitors (GR157368, GR166081, GR167088, and GR179849) are representatives of a series utilizing a novel 5, 5-trans-lactone template to specifically acylate Ser195 of thrombin, resulting in an acyl complex. In each case the crystal structure of the complex reveals a binding mode which is consistent with the formation of a covalent bond between the ring-opened lactone of the inhibitor and residue Ser195. Improvements in potency and selectivity of these inhibitors for thrombin are rationalized on the basis of the observed protein/inhibitor interactions identified in these complexes. Occupation of the thrombin S2 and S3 pockets is shown to be directly correlated with improved binding and a degree of selectivity. The binding mode of GR179849 to thrombin is compared with the thrombin/PPACK complex [Bode, W., Turk, D., and Karshikov, A. (1992) Protein Sci. 1, 426-471] as this represents the archetypal binding mode for a thrombin inhibitor. This series of crystal structures is the first to be reported of synthetic, nonpeptidic acylating inhibitors bound to thrombin and provides details of the molecular recognition features that resulted in nanomolar potency.

Binding Sites↗
PubMed2000

Crystal structures of the complexes of trichosanthin with four substrate analogs and catalytic mechanism of RNA N-glycosidase.

Four substrate analogs-nicotinamide adenine dinucleotide, adenylyl (3', 5') guanosine, guanylyl (3',5') adenosine, and adenosine 2', 5'-diphosphate-have been used to prepare the complexes with trichosanthin (TCS), a type I ribosome-inactivating protein that possesses the activity of N-glycosidase. The crystal structures of the complexes have been determined and refined at high resolution. The refined structures show that the N-glycosidic bonds of all the four substrate analogues are hydrolyzed and a common structure is shared by the four complexes, in which only adenine, the product of the enzymatic reaction, is bound in the active center. The structure is compared with those of native trichosanthin and a previously reported trichosanthin-NADPH complex in which the N-glycosidic bond is uncleaved. The structural comparison shows that the conformation of Tyr70 obviously differs from those in the latter two structures, i.e., the side chain of Tyr70 is rotated along its Cbeta-Cgamma bond by approximately 70 degrees. The water molecule found to be preassociated with the N-glycosidic bond in the TCS-NADPH complex structure and proposed to be the water candidate responsible for hydrolyzing the N-glycosidic bond disappears in the trichosanthin-product complex structure. Based on the comparison of the three structures representing the different stages of the enzymatic reaction, the catalytic mechanism of RNA N-glycosidase has been further elucidated. Proteins 2000;39:37-46.

Adenosine Diphosphate↗