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At least 1,153 records · Page 64Linked to original sources
PubMed2005

Kinetic and crystallographic studies on 2-(beta-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site.

In an attempt to identify leads that would enable the design of inhibitors with enhanced affinity for glycogen phosphorylase (GP), that might control hyperglycaemia in type 2 diabetes, three new analogs of beta-D-glucopyranose, 2-(beta-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole were assessed for their potency to inhibit GPb activity. The compounds showed competitive inhibition (with respect to substrate Glc-1-P) with K(i) values of 145.2 (+/-11.6), 76 (+/-4.8), and 8.6 (+/-0.7) muM, respectively. In order to establish the mechanism of this inhibition, crystallographic studies were carried out and the structures of GPb in complex with the three analogs were determined at high resolution (GPb-methyl-oxadiazole complex, 1.92 A; GPb-benzothiazole, 2.10 A; GPb-benzimidazole, 1.93 A). The complex structures revealed that the inhibitors can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure, and provide a rationalization for understanding variations in potency of the inhibitors. In addition, benzimidazole bound at the new allosteric inhibitor or indole binding site, located at the subunit interface, in the region of the central cavity, and also at a novel binding site, located at the protein surface, far removed (approximately 32 A) from the other binding sites, that is mostly dominated by the nonpolar groups of Phe202, Tyr203, Val221, and Phe252.

Benzimidazoles↗
PubMed1996

Hailey-Hailey disease keratinocytes: normal assembly of cell-cell junctions in vitro.

The blisters in the inherited disorder, Hailey-Hailey disease, may be caused by defective epidermal junctional complexes. We evaluated these structural complexes in vivo and in vitro. We induced a vesicular lesion in the apparently normal skin of a patient with Hailey-Hailey disease and studied a biopsy of this lesion by transmission electron microscopy. To determine whether acantholysis was related to a defect in the number or assembly of intercellular junctions, we cultured Hailey-Hailey disease keratinocytes in medium containing 0.1 mM Ca2+ and increased the [Ca2+] to 1.1 mM in order to induce assembly of cell-cell junctions. Keratinocytes were examined by double immunofluorescence with antibodies to the desmosome protein, desmoplakin, and the adherens junction protein, vinculin, at intervals after the increase in [Ca2+]. Characteristic Hailey-Hailey disease histopathology was observed by electron microscopy of the patient's skin after trauma, but we found no splitting of desmosomes. Based on the location, intensity, and rate of change of immunofluorescent staining, Hailey-Hailey and normal keratinocytes did not differ in their ability to assemble desmosomes and adherens junctions. Furthermore, we observed no significant morphologic differences between normal and Hailey-Hailey keratinocytes cultured in low and high [Ca2+]-containing media; Hailey-Hailey cells contained abundant normal-appearing desmosomes in 1.1 mM [Ca2+]. Since Hailey-Hailey disease keratinocytes can assemble normal-appearing adherens junctions and desmosomes in vitro, the functional defect may not lie in assembly of cell-cell adhering junctions, or additional perturbation may be required to expose the defect.

Adult↗
PubMed1977

The crystal structure of complexes between horse liver alcohol dehydrogenase and the coenzyme analogues 3-iodopyridine-adenine dinucleotide and pyridine-adenine dinucleotide.

We have studied the binding of the enzymatically active NAD+ analogue, 3-iodopyridine-adenine dinucleotide, and the inactive analogue, pyridine-adenine dinucleotide to the enzyme horse liver alcohol dehydrogenase using X-ray crystallographic methods. These studies were made under such conditions that crystals of the complexes were isomorphous to apoenzyme crystals. Both analogues bind in the same conformation. The binding of the adenosine moiety is very similar to that of ADP-ribose or NADH bound to the enzyme. The conformation and mode of binding of the remaining portions of the analogue molecules is, however, quite different. The pyridine ring is not situated in the active-site pocket as the nicotinamide group in the isomorphous enzyme-NADH-imidazole complex but lies at the surface of the crevice between the two domains of the subunit, approximately 1.5 nm away from the catalytically active zinc atom. Lys-228 which has been shown to be important for NADH dissociation is in this region of the molecule.

Alcohol Oxidoreductases↗
PubMed1984

A murine T cell receptor gene complex: isolation, structure and rearrangement.

We describe here our efforts to develop a systematic strategy for the enumeration and isolation of genes encoding T cell-specific, membrane-associated polypeptides. Of particular importance among the cDNA clones that we have isolated is one which encodes the beta chain of the murine T cell receptor for antigen. The gene product is strikingly similar to immunoglobulin in its variable (V), constant (C), joining (J), and diversity (D) - like elements and the ability of the latter three types of element to assort independently during differentiation. The genomic organization of the constant region locus which encodes this molecule consists of two tandemly arrayed units of the form JC/JC, where the J clusters consist of fourteen distinct elements, many of which may be functional. The two constant regions differ by only four amino acids and both are apparently expressed in T cells of the same phenotype, so they probably do not represent isotypes in the classical sense. The sequences flanking the V, D and J elements are also similar to the conserved heptamer and nonomer sequences of immunoglobulins thought to be important in the recombination of the specific gene segments. These similarities indicate both the common evolutionary origins of these loci and the strong selective pressure that must be operative. The T cell receptor locus differs somewhat from immunoglobulins in the large number of possible J region elements and to some extent in the hypervariable-framework regions of the V region. We and others have mapped this gene to chromosome 6 of the mouse, in the same portion of the chromosome but not closely linked the kappa locus. The significance of the predicted protein structure of the beta chain and its support of the one-receptor model of MHC-antigen recognition are discussed.

Amino Acid Sequence↗
PubMed2006

Complex genetic structures with repeated elements, a sul-type class 1 integron, and the blaVEB extended-spectrum beta-lactamase gene.

Two clinical isolates of Pseudomonas aeruginosa, TL-1 and TL-2, were isolated from a patient transferred from Bangladesh and hospitalized for osteomyelitis in Paris, France. P. aeruginosa TL-1 expressed the extended-spectrum beta-lactamase VEB-1a and was susceptible only to imipenem and colistin, while P. aeruginosa TL-2 expressed only the naturally occurring bla(AmpC) gene at a basal level and exhibited a wild-type beta-lactam resistance phenotype. In TL-1, the typical 5'-end conserved sequence (5'-CS) region of class 1 integrons usually present upstream of the bla(VEB-1a) gene was replaced by a truncated 3'-CS and a 135-bp repeated element (Re). Downstream of the bla(VEB-1a) gene, an insertion sequence, ISPa31 disrupted by ISPa30, and an orf513 sequence, belonging to a common region (conserved region 1 [CR1]) immediately upstream of the aphA-6 gene, were present. Further downstream, a second truncated 3'-CS region in direct repeat belonged to In51, an integron containing two gene cassettes (aadA6 and the OrfD cassette). Thus, the overall structure corresponded to a sul-type class 1 integron termed In121. Genetic analyses revealed that both isolates were clonally related and differed by a ca. 100-kb fragment that contained In121. Both isolates contained another integron, In122, that carried three gene cassettes: aadB, dfrA1, and the OrfX cassette. This work identifies for the first time the spread of Re-associated bla(VEB) genes located on a sul-type integron. It also reports for the first time a CR1 element in P. aeruginosa that is associated with an aminoglycoside resistance aphA-6 gene that is expressed from a composite promoter.

Alleles↗
PubMed2006

The genome of the obligately intracellular bacterium Ehrlichia canis reveals themes of complex membrane structure and immune evasion strategies.

Ehrlichia canis, a small obligately intracellular, tick-transmitted, gram-negative, alpha-proteobacterium, is the primary etiologic agent of globally distributed canine monocytic ehrlichiosis. Complete genome sequencing revealed that the E. canis genome consists of a single circular chromosome of 1,315,030 bp predicted to encode 925 proteins, 40 stable RNA species, 17 putative pseudogenes, and a substantial proportion of noncoding sequence (27%). Interesting genome features include a large set of proteins with transmembrane helices and/or signal sequences and a unique serine-threonine bias associated with the potential for O glycosylation that was prominent in proteins associated with pathogen-host interactions. Furthermore, two paralogous protein families associated with immune evasion were identified, one of which contains poly(G-C) tracts, suggesting that they may play a role in phase variation and facilitation of persistent infections. Genes associated with pathogen-host interactions were identified, including a small group encoding proteins (n = 12) with tandem repeats and another group encoding proteins with eukaryote-like ankyrin domains (n = 7).

Animals↗
PubMed2006

The genome of Oscheius tipulae: determination of size, complexity, and structure by DNA reassociation using fluorescent dye.

This work describes the physicochemical characterization of the genome and telomere structure from the nematode Oscheius tipulae CEW1. Oscheius tipulae is a free-living nematode belonging to the family Rhabditidae and has been used as a model system for comparative genetic studies. A new protocol that combines fluorescent detection of double-stranded DNA and S1 nuclease was used to determine the genome size of O. tipulae as 100.8 Mb (approximately 0.1 pg DNA/haploid nucleus). The genome of this nematode is made up of 83.4% unique copy sequences, 9.4% intermediate repetitive sequences, and 7.2% highly repetitive sequences, suggesting that its structure is similar to those of other nematodes of the genus Caenorhabditis. We also showed that O. tipulae has the same telomere repeats already found in Caenorhabditis elegans at the ends and in internal regions of the chromosomes. Using a cassette-ligation-mediated PCR protocol we were able to obtain 5 different putative subtelomeric sequences of O. tipulae, which show no similarity to C. elegans or C. briggsae subtelomeric regions. DAPI staining of hermaphrodite gonad cells show that, as detected in C. elegans and other rhabditids, O. tipulae have a haploid complement of 6 chromosomes.

Animals↗
PubMed2002

Tissue engineering of complex tooth structures on biodegradable polymer scaffolds.

Tooth loss due to periodontal disease, dental caries, trauma, or a variety of genetic disorders continues to affect most adults adversely at some time in their lives. A biological tooth substitute that could replace lost teeth would provide a vital alternative to currently available clinical treatments. To pursue this goal, we dissociated porcine third molar tooth buds into single-cell suspensions and seeded them onto biodegradable polymers. After growing in rat hosts for 20 to 30 weeks, recognizable tooth structures formed that contained dentin, odontoblasts, a well-defined pulp chamber, putative Hertwig's root sheath epithelia, putative cementoblasts, and a morphologically correct enamel organ containing fully formed enamel. Our results demonstrate the first successful generation of tooth crowns from dissociated tooth tissues that contain both dentin and enamel, and suggest the presence of epithelial and mesenchymal dental stem cells in porcine third molar tissues.

Absorbable Implants↗
PubMed2004

pdb-care (PDB carbohydrate residue check): a program to support annotation of complex carbohydrate structures in PDB files.

BACKGROUND: Carbohydrates are involved in a variety of fundamental biological processes and pathological situations. They therefore have a large pharmaceutical and diagnostic potential. Knowledge of the 3D structure of glycans is a prerequisite for a complete understanding of their biological functions. The largest source of biomolecular 3D structures is the Protein Data Bank. However, about 30% of all 1663 PDB entries (version September 2003) containing carbohydrates comprise errors in glycan description. Unfortunately, no software is currently available which aligns the 3D information with the reported assignments. It is the aim of this work to fill this gap. RESULTS: The pdb-care program http://www.glycosciences.de/tools/pdb-care/ is able to identify and assign carbohydrate structures using only atom types and their 3D atom coordinates given in PDB-files. Looking up a translation table where systematic names and the respective PDB residue codes are listed, both assignments are compared and inconsistencies are reported. Additionally, the reliability of reported and calculated connectivities for molecules listed within the HETATOM records is checked and unusual values are reported. CONCLUSION: Frequent use of pdb-care will help to improve the quality of carbohydrate data contained in the PDB. Automatic assignment of carbohydrate structures contained in PDB entries will enable the cross-linking of glycobiology resources with genomic and proteomic data collections.

Carbohydrate Conformation↗
PubMed1992

Cholesterol pools in rat adrenal mitochondria: use of cholesterol oxidase to infer a complex pool structure.

ACTH stimulates the side-chain cleavage of cholesterol in the adrenal cortex in a cycloheximide-inhibitable manner. Its mechanism involves mobilizing cholesterol to a "steroidogenic pool" where the sterol can be metabolized to pregnenolone. This pool has been proposed to be in the inner mitochondrial membrane where cytochrome P-450scc resides, and regulation may involve transport of cholesterol from the outer to the inner membrane. To investigate the structure of the mitochondrial cholesterol pools, cholesterol oxidase has been used as a membrane-impermeant probe which should have selective access to outer membrane cholesterol. At 37 C, almost all the cholesterol in mitochondria from ether-stressed rats was metabolized by cholesterol oxidase. Depletion of an intermembrane space but not a matrix marker enzyme indicated partial disruption of the outer membrane. However, at 16 C, mitochondria remained largely intact, and cholesterol oxidase identified a unique pool of cholesterol, which was about two-thirds of the total. In experiments using mitochondria from ether-stressed rats, the size of the 16 C cholesterol oxidase accessible and inaccessible pools was compared with that of the steroidogenic pool. The steroidogenic pool was enhanced by pretreatment of some animals with aminoglutethimide (a P-450scc inhibitor) or eliminated with cycloheximide, both of which increased the total mitochondrial cholesterol. This approach reveals that the steroidogenic pool is not equivalent to the cholesterol oxidase-inaccessible pool. Rather, it overlaps both the cholesterol oxidase accessible and inaccessible pools. These results are not consistent with a simple two pool model, but can be explained by assuming a minimum of three cholesterol pools.

Adrenal Cortex↗
PubMed1981

BBM-928, a new antitumor antibiotic complex. III. Structure determination of BBM-928 A, B and C.

Structures of antitumor antibiotics BBM-928 A, B and C have been determined. They are cyclic decadepsipeptides containing 3-hydroxy-6-methoxyquinaldic acid as a chromophore. Two amino acids, not found in nature, L-beta-hydroxyl-N-methylvaline and trans-(3S,4S)-4-hydroxy-2,3,4,5-tetrahydropyridazine-3-carboxylic acid, were identified as structural constituents of the antibiotic. In gross structure, BBM-928 resembles the echinomycin group of antibiotics which are cyclic octadepsipeptides having a quinoxaline chromophore, but BBM-928 differs from the latter group by virtue of the lack of a sulfur-containing cross linkage.

Antibiotics, Antineoplastic↗
PubMed1983

Bu-2470, a new peptide antibiotic complex. II. Structure determination of Bu-2470 A, B1, B2a and B2b.

The structures of Bu-2470 A, B1, B2a, and B2b have been determined. Bu-2470 A is a simple octapeptide having no fatty acid moiety, while Bu-2470 B1, B2a and B2b are octapeptides that have been acylated with a beta-hydroxy C11 or C10 fatty acid. The octapeptide structure of Bu-2470 components was found identical with that of octapeptin C1, hence generic names of octapeptin C0, C2, C3 and C4 are proposed for Bu-2470 A, B1, B2a and B2b, respectively.

Amidohydrolases↗