PubMed Health⌕ Search

Biomedical subjects

A Bergner

Publications and source records attributed to A Bergner.

At least 37 records · Page 2Linked to original sources
PubMed1997

Mechanism of inhibition of the human matrix metalloproteinase stromelysin-1 by TIMP-1.

Matrix metalloproteinases (MMPs) are zinc endopeptidases that are required for the degradation of extracellular matrix components during normal embryo development, morphogenesis and tissue remodelling. Their proteolytic activities are precisely regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance results in diseases such as arthritis, atherosclerosis, tumour growth and metastasis. Here we report the crystal structure of an MMP-TIMP complex formed between the catalytic domain of human stromelysin-1 (MMP-3) and human TIMP-1. TIMP-1, a 184-residue protein, has the shape of an elongated, contiguous wedge. With its long edge, consisting of five different chain regions, it occupies the entire length of the active-site cleft of MMP-3. The central disulphide-linked segments Cys 1-Thr 2-Cys 3-Val 4 and Ser 68-Val 69 bind to either side of the catalytic zinc. Cys 1 bidentally coordinates this zinc, and the Thr-2 side chain extends into the large specificity pocket of MMP-3. This unusual architecture of the interface between MMP-3 and TIMP-1 suggests new possibilities for designing TIMP variants and synthetic MMP inhibitors with potential therapeutic applications.

Binding Sites↗
PubMed1997

Ta6Br(2+)12, a tool for phase determination of large biological assemblies by X-ray crystallography.

The title compound Ta6Br(2+)12 is of interest for the analysis of biological structures as a heavy-metal derivative with great potential for the structure determination of large protein systems. In macromolecular crystallography the phases of the measured structure factor amplitudes have to be determined. The most widely used method for novel structures is isomorphous replacement by introducing electron-rich compounds into the protein crystals. These compounds produce measurable changes of the diffraction intensities, which allow phase determination. We synthetized the Ta6Br(2+)12 cluster in high yields, crystallized it, and determined its crystal structure by X-ray diffraction analysis at atomic resolution. The cluster is a regular octahedron consisting of six metal atoms with 12 bridging bromine atoms along the 12 edges of the octahedron. The cluster is compact, of approximately spherical shape with about 4.3 A radius and highly symmetrical. One Ta6Br(2+)12 ion adds 856 electrons to a protein, a considerable contribution to the scattering power even of large proteins or multimeric systems. At low resolution all atoms of the cluster scatter in phase and act as a super heavy-atom, which is easy to locate in the difference Patterson map. We investigated its binding sites in the biologically significant high-resolution structures of an antibody V(L) domain, dimethyl sulfoxide reductase, GTP-cyclohydrolase I, and the proteasome. With the randomly oriented cluster, treated as a single site scatterer, phases could be used only up to 6 A resolution. In contrast, when the cluster is correctly oriented, phases calculated from its 18 atom sites can be used to high resolution. We present the atomic structure of the Ta6Br(2+)12, describe a method to determine its localization and orientation in the unit cell of protein crystals of two different proteins, and analyse its phasing power. We show that phases can be calculated to high resolution. The phase error is lower by more than 30 degrees compared to the single site approximation, using a resolution of 2.2 A. Furthermore, Ta6Br(2+)12 has two different strong anomalous scatterers tantalum and bromine to be used for phase determination.

Binding Sites↗
PubMed1996

Crystal structure of a coagulogen, the clotting protein from horseshoe crab: a structural homologue of nerve growth factor.

The clotting cascade system of the horseshoe crab (Limulus) is involved in both haemostasis and host defence. The cascade results in the conversion of coagulogen, a soluble protein, into an insoluble coagulin gel. The clotting enzyme excises the fragment peptide C from coagulogen, giving rise to aggregation of the monomers. The crystal structure of coagulogen reveals an elongated molecule that embraces the helical peptide C fragment. Cleavage and removal of the peptide C would expose an extended hydrophobic cove, which could interact with the hydrophobic edge of a second molecule, leading to a polymeric fibre. The C-terminal half of the coagulogen molecule exhibits a striking topological similarity to the neurotrophin nerve growth factor (NGF), providing the first evidence for a neurotrophin fold in invertebrates. Similarities between coagulogen and Spatzle, the Drosophila ligand of the receptor Toll, suggest that the neurotrophin fold might be considered more ancient and widespread than previously realized.

Amino Acid Sequence↗
PubMed1996

The structure of recombinant human annexin VI in crystals and membrane-bound.

The crystal structure of calcium-free recombinant human annexin VI was solved at a resolution of 3.2 A by using the annexin I model for Patterson search and refined to an R-factor of 19.0%. The molecule consists of two similar halves closely resembling annexin I connected by an alpha-helical segment and arranged perpendicular to each other. The calcium and membrane binding sites assigned by structural homology are therefore not located in the same plane. Analysis of the membrane-bound form of annexin VI by electron microscopy shows the two halves of the molecule coplanar with the membrane, but oriented differently to the crystal structure and suggesting a flexible arrangement. Ion channel activity has been found for annexin VI and the half molecules by electrophysiological experiments.

Annexin A6↗
PubMed1995

The X-ray crystal structure of thrombin in complex with N alpha-2-naphthylsulfonyl-L-3-amidino-phenylalanyl-4-methylpiperidide: the beneficial effect of filling out an empty cavity.

The 2.5 Angstrum structure of bovine epsilon-thrombin in complex with N alpha-2-naphthyl-sulfonyl-L-3-amidinophenylalanyl-4-methylpiper idide (L-NAPAMP) was solved and crystallographically refined to an R-value of 0.19. The L-NAPAMP moiety is completely and unambiguosly defined in the electron density. NAPAMP binds almost identical to the related 4-methyl deficient 3-amidino-phenylalanyl derivative TAPAP. The overall binding geometry appears dominated by the fixation of the 3-amidinophenyl ring in thrombin's S1-pocket and the hydrogen bonds to Gly 216, irrespective of the presence or absence of a substituent in the 4-position of the piperidine ring. The additional 4-methyl group gives rise to a 17-fold better binding. The more complete spatial occupancy of the hydrophobic S2-cavity therefore accounts for a decrease in free energy of binding of 15 kcal/mol, a value comparable with that anticipated for filling up a stable empty cavity of similar size by a methyl group.

Alanine↗
PubMed1989

Blood glucose turnover during high- and low-intensity exercise.

We hypothesized that whole body glucose uptake (Rd) during exercise is not related in a simple, linear manner to O2 uptake (VO2). To test this, seven healthy male subjects (age range 23-34 yr) were studied in the postabsorptive but not glycogen-depleted state. Three conditions were examined: 1) rest, 2) 40 min of constant exercise in which the work rates were carefully chosen to consist of low-intensity exercise (no elevated blood lactate, a mean of 40% maximal VO2), and 3) 40 min of high-intensity exercise (markedly elevated blood lactate, 79% maximal VO2). Gas exchange was measured breath by breath, and glucose uptake and production were measured using [6,6-2H2]glucose. Low-intensity exercise (n = 7) resulted in a small but not statistically significant increase in mean Rd [3.06 +/- 0.37 (SE) mg.min-1.kg-1] compared with resting values (2.87 +/- 0.39 mg.min-1.kg-1) despite a fourfold increase in the production of CO2 and VO2. By contrast, the high-intensity exercise Rd (n = 5, 6.98 +/- 0.67 mg.min-1.kg-1) was significantly greater than the resting value (3.03 +/- 0.56 mg.min-1.kg-1). Results of glucose production were virtually the same. Similarly, mean levels of epinephrine and norepinephrine increased significantly above resting values during high- but not low-intensity exercise. Our data demonstrate that whole body glucose dynamics and regulation during 40 min of exercise do not change in a simple linear manner with respect to metabolic rate.

Adult↗
PubMed1987

Antireflux treatment for asthma. Improvement in patients with associated gastroesophageal reflux.

Fifteen patients with both nonallergic asthma and symptomatic gastroesophageal reflux were studied before and after an eight-week period of vigorous antireflux therapy, which included ranitidine hydrochloride, 150 mg twice a day. Pulmonary and esophageal symptoms were recorded on daily diary cards. Therapy was associated with prompt amelioration of reflux symptoms and with a less dramatic and more delayed improvement in pulmonary symptoms. Objectively, esophageal erosions healed completely in eight of the ten patients who had them at the beginning of the trial, and pulmonary function measurements improved significantly. Intraesophageal infusions of physiologic saline and 0.1N hydrochloric acid in patients and healthy controls did not significantly alter pulmonary function, as measured by standard spirometry. There is a subset of patients in whom bronchoconstriction is triggered by gastroesophageal reflux. Treatment of reflux in such patients may improve their asthma.

Adult↗
PubMed1987

Safety and efficacy of loratadine (Sch-29851): a new non-sedating antihistamine in seasonal allergic rhinitis.

Loratadine, a new antihistamine in the non-sedating class, was evaluated for efficacy and safety in treatment of allergic rhinitis in a multicentered study. Loratadine was found to be both safe and efficacious. When administered to patients with seasonal allergic rhinitis, a single daily oral dose of 10 mg is comparable in efficacy to clemastine, 1 mg, given twice daily. The incidence of sedation with loratadine is comparable to placebo and significantly lower than with clemastine. The incidence of anticholinergic side effects with loratadine is low and in this study was comparable to placebo and clemastine.

Capsules↗
PubMed1985

Marked peripheral eosinophilia: a clue to allergic bronchopulmonary aspergillosis in office practice.

Allergic Bronchopulmonary Aspergillosis (ABPA) is not rare. A diagnosis of "clinically probable ABPA" should be suspected in asthmatics who are not well controlled on adequate bronchodilators, who are steroid dependent or who have recurrent pulmonary infiltrates, and who also have a positive skin test with a separate aspergillus extract. Suspicion should also stimulate pursuit of this diagnosis in asthmatics with a total eosinophil count over 500 cells/mm3 or a total serum IgE level over 1,000 IU/ml. Early detection in office practice is feasible, practical, and may be critical to avoidance of permanent pulmonary damage.

Adolescent↗
PubMed1977

Outpatient management of asthma.

Oral administration of xanthine compounds represents the first line of therapy in most patients with asthma. Establishment and maintenance of a therapeutic blood level of the medication requires regular dosgae. Oral sympathomimetic agents with predominantly beta-2 adrenergic activity, if tolerated, are often useful adjuncts to xanthine therapy. Sympathomimetic aerosols are not recommended. Cromolyn is often a valuable prophlactic agent. Corticosteroid aerosols may be useful in limiting adrenal suppression when steroids are necessary.

Adrenal Cortex Hormones↗
PubMed1975

Pulmonary hypersensitivity associated with pancreatin powder exposure.

A 25-year-old woman with obstructive, reversible pulmonary and nasal hypersensitivity apparently induced by casual, repeated inhalation of pancreatin powder (desiccated pork pancreas) is described. The powder was being employed as a dietary supplement for the patient's son, diagnosed as having cystic fibrosis. Two challenges of the diagnosed as having cystic fibrosis. Two challenges of the patient by reproducing home use of the powder resulted in repetition of a hypersensitivity symptom complex on both occasions. Vitalometry demonstrated an immediate and late response. Avoidance of pancreatin powder exposure resulted in subsidence of symptoms. Immunologic mechanisms are suggested but not proven.

Adult↗
PubMedDate not supplied

Use of Relibase for retrieving complex three-dimensional interaction patterns including crystallographic packing effects.

Relibase is a database system that has been specially designed to handle protein-ligand data. Included within Relibase is a tool that can be used to systematically analyse protein-ligand interaction patterns specified by three-dimensional (3D) constraints, revealing favorable combinations of interacting functional groups and their preferred interaction geometries. This paper describes the Relibase 3D query tools, including novel extensions (Relibase+) for handling crystallographic packing effects. Examples illustrating the broad range of functionality for defining 3D interaction patterns and the application of such queries in drug design comprise carbonyl-carbonyl interactions, zinc binding site environments, and ligand-ligand interactions in the crystal packing.

Binding Sites↗
PubMedDate not supplied

Genotoxicity of nitroso compounds and sodium dichromate in a model combining organ cultures of human nasal epithelia and the comet assay.

Genotoxic effects of xenobiotics are a possible step in tumor initiation in the mucosa of the upper aerodigestive tract. Using the comet assay, detecting genotoxicity in human tissue has been restricted to single incubations in vitro, but in vivo most xenobiotics harm their target in a repetitive or chronic manner. Therefore, we propose a model, which provides repetitive incubations in human upper aerodigestive tract mucosa cultures. Samples of human inferior nasal turbinate mucosa (n = 25) were cultured according to a modified version of a technique originally described by Steinsvåg. On day 1 fresh samples and on days 7, 9 and 11 organ cultures were incubated with N-nitrosodiethylamine (NDEA), sodium dichromate (Na2Cr2O7) and N'-methyl-N-nitro-N-nitrosoguanidine (MNNG). Mucosa samples and organ cultures, respectively, underwent a modified comet assay on days 1, 7 and 11. Genotoxicity could be shown for NDEA, Na2Cr2O7 and MNNG on days 1, 7 and 11. Duration of tissue culture and repetitive incubations did not significantly influence the results for NDEA. Nevertheless, Na2Cr2O7 and MNNG caused higher genotoxic effects on cultures subjected to the comet assay on day 11. This model may help to assess genotoxic hazards posed by environmental pollutants that have a cumulative character in repetitive or chronic exposure in vivo.

Adult↗
PubMedDate not supplied

The suitability of Ta6Br12(2+) for phasing in protein crystallography.

The title compound Ta6Br12(2+) is of interest for the analysis of biological structures as a heavy metal derivative with great potential for the structure determination of large protein systems. In macromolecular crystallography the phases of the measured structure factor amplitudes have to be determined by compounds that produce measurable changes of the diffraction intensities. Ta6Br12(2+) uniquely meets the demands of a heavy metal derivative and is an important tool for phase determination, especially considering the structure determination of large protein systems.

Bromides↗