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PubMed2006

Engineered site-directed labeling of nicotinic acetylcholine receptors using reactive epibatidine derivatives: appraisal of epibatidine-docking models in neuronal and muscular receptors.

We developed an engineered site-directed labeling method (Foucaud et al., 2001) to investigate ligand receptor interactions on the acetylcholine (ACh)- binding site of nicotinic acetylcholine receptors (nAChRs). The method uses cysteine receptor mutants, together with cysteine-reactive ligand analogs, to generate a site-directed covalent reaction within the binding site. We selected epibatidine (EPB) as a prototypical ligand, acting at all types of nAChRs with sufficient affinity to allow this study. Accordingly, we synthesized three cysteine-reactive derivatives, all modified at the C-3 of the pyridine ring of the alkaloid with NCS; -NHCOCH2Cl, and -CH2Cl groups, respectively (Fig. 1). The binding properties have been established on rat brain, alpha7-5HT3 chimera, and Torpedo membranes, respectively, whereas the functional properties were tested on alpha4beta2 and alpha7 receptor expressed in oocytes and Cys-less muscular receptor expressed in HEK cells (Sakr et al., 2005).

Animals↗
PubMed2004

Knowledge-based elastic potentials for docking drugs or proteins with nucleic acids.

Elastic ellipsoidal functions defined by the observed hydration patterns around the DNA bases provide a new basis for measuring the recognition of ligands in the grooves of double-helical structures. Here a set of knowledge-based potentials suitable for quantitative description of such behavior is extracted from the observed positions of water molecules and amino acid atoms that form hydrogen bonds with the nitrogenous bases in high resolution crystal structures. Energies based on the displacement of hydrogen-bonding sites on drugs in DNA-crystal complexes relative to the preferred locations of water binding around the heterocyclic bases are low, pointing to the reliability of the potentials and the apparent displacement of water molecules by drug atoms in these structures. The validity of the energy functions has been further examined in a series of sequence substitution studies based on the structures of DNA bound to polyamides that have been designed to recognize the minor-groove edges of Watson-Crick basepairs. The higher energies of binding to incorrect sequences superimposed (without conformational adjustment or displacement of polyamide ligands) on observed high resolution structures confirm the hypothesis that the drug subunits associate with specific DNA bases. The knowledge-based functions also account satisfactorily for the measured free energies of DNA-polyamide association in solution and the observed sites of polyamide binding on nucleosomal DNA. The computations are generally consistent with mechanisms by which minor-groove binding ligands are thought to recognize DNA basepairs. The calculations suggest that the asymmetric distributions of hydrogen-bond-forming atoms on the minor-groove edge of the basepairs may underlie ligand discrimination of G.C from C.G pairs, in addition to the commonly believed role of steric hindrance. The analysis of polyamide-bound nucleosomal structures reveals other discrepancies in the expected chemical design, including unexpected contacts to DNA and modified basepair targets of some ligands. The ellipsoidal potentials thus appear promising as a mathematical tool for the study of drug- and protein-DNA interactions and for gaining new insights into DNA-binding mechanisms.

Algorithms↗
PubMed2006

Enantioselective substrate binding in a monooxygenase protein model by molecular dynamics and docking.

The two-component flavoenzyme styrene monooxygenase (SMO) is an efficient alternative to several chemical epoxidation catalysts on a preparative scale. A first homology model of the catalytic domain (StyA) of SMO was constructed (Protein Data Bank ID 2HD8) based on the structure of para-hydroxybenzoate hydroxylase. The StyA protein structure was optimized by restrained molecular dynamics to reproduce specific pre-S binding orientations of styrene. Effects of all 10 point mutations examined were explained by the distance of the site to the styrene and FAD binding sites. Thirteen of 20 ligands could be accommodated in a catalytically active binding orientation, and predicted affinities correlated well with experimental turnover and inhibition. The binding cavity is almost completely hydrophobic except for a hydrogen-bonded network formed by three water molecules, the backbone of residues 300-302, and the flavin ribityl, similar to P293, and three crystal waters in para-hydroxybenzoate hydroxylase suggest that P302, T47, and the waters in StyA are a vital component of the catalytic mechanism. The current optimized and validated StyA model provides a good starting point for elucidation of the structural basis of StyA ligand binding and catalysis. Novel insights in the binding of ligands to SMO/StyA, provided by the current protein model, will aid the rational design of mutants with specific, altered enantioselective properties.

Binding Sites↗
PubMed1993

Home ranges of feral cats at Avonmouth Docks (United Kingdom).

The feral cat population at a 178 ha dockland site was studied for eighteen months using direct observation assisted by radio-tracking. Though food appeared to be abundant and widely distributed, the population density was low (10-15 adults/km2). Home ranges were similar for males and females, and were much smaller (15 +/- 17 ha and 10 +/- 7 ha, respectively) than would be expected from the low density. The implications of the findings for feral cat control were discussed, with particular emphasis on rabies emergency measures.

Animals↗
PubMed2006

Receptor-based computational screening of compound databases: the main docking-scoring engines.

The processes used by academic and industrial scientists to discover new drugs have recently experienced a true renaissance with many new and exciting techniques. The number of protein structures and/or chemical ligands is constantly growing, through the use of parallel chemistry, X-ray crystallography, NMR or homology modeling methods and so is the theoretical understanding of protein-ligand interactions. As such, structure-based approaches to drug-design and in silico screening are becoming routine part of most modern lead discovery programs. Prioritization of compound libraries is an extremely important task that aims at the rapid identification of tight-binding ligands and ultimately new therapeutic compounds. These in silico approaches combined with other experimental methods facilitate the design of new medicines to treat cardiovascular, degenerative, infectious, and neoplastic diseases, among others. Here, we review key concepts and specific features of several selected ligand-receptor docking/scoring methods while several other topics pertaining to the field of in silico screening are reviewed in the following articles of this special issue of Current Protein and Peptide Science.

Animals↗
PubMed2002

Responses to tail docking in calves and heifers.

The primary objective of this study was to determine the behavioral and physiological effects of tail banding and atrophy using rubber rings 2 to 4 mo before first parturition in dairy heifers either with or without the use of epidural anesthesia. The secondary objective was to determine behavioral responses to tail banding using rubber rings in calves 7 to 42 d of age. Preparturient heifers (n = 24) were randomly assigned to one of four treatment groups: 1) tails were cleaned and handled; 2) tails were cleaned, handled, and an elastrator band was applied to the tail; 3) an epidural was administered 15 min before cleaning and handling; and 4) an epidural was administered 15 min before application of an elastrator band. Behavioral observations and physiological responses were collected for 6 wk. Additionally, behavioral responses to tail banding were recorded for 10 d on Holstein heifer calves that were 1 to 6 wk of age (n = 40). No significant differences in behavior were observed among treatment groups of preparturient heifers at any time during the 6-wk observation period. Preweaned calves that were 21 to 42 d of age demonstrated significantly more restlessness after application of tail bands compared to younger calves or control calves of the same age. Plasma cortisol values of preparturient heifers remained within limits previously described for nonstressed animals and no significant differences were detected among groups. Hematological values remained within the reference values for cattle, and there were no significant differences between groups except for relatively more eosinophils in the heifers that received epidurals. No significant differences in heart rate or body temperature were detected among groups.

Amputation, Surgical↗
PubMed2006

Cutting edge: Epstein-Barr virus transactivates the HERV-K18 superantigen by docking to the human complement receptor 2 (CD21) on primary B cells.

EBV, a ubiquitous human herpesvirus, is the causative agent of infectious mononucleosis and is associated with many carcinomas. We have previously shown that the EBV latent genes LMP-1 and LMP-2A (for latent membrane proteins 1 and 2A), transactivate a human endogenous retrovirus (HERV), HERV-K18, in infected B lymphocytes. The envelope (Env) protein of HERV-K18 encodes a superantigen that strongly stimulates a large number of T cells. In this study we report that HERV-K18 env is transactivated even earlier in the infection process, before the establishment of latency; namely, we found that EBV, through its interaction with its cellular receptor CD21, induces the HERV-K18 env gene in resting B lymphocytes. This transactivation is direct and immediate, as up-regulation of transcripts can be detected within 30 min after EBV exposure. Thus, EBV binding to human CD21 on resting B cells triggers the expression of an endogenous superantigen. The biological significance of this superantigen expression for the EBV life cycle is discussed.

Animals↗
PubMed1986

Mortality and cancer incidence among Swedish dock workers--a retrospective cohort study.

The study originates from the arousal of suspicions that, in connection with loading and unloading work involving the use of trucks, exposure to diesel exhaust fumes may be carcinogenic. This report describes a register study in which a broad mapping of the cause-of-death pattern and cancer morbidity has been carried out through the matching of locally compiled personal data with those from a central register, the Cause-of-Death Register, and the Cancer Register. The results obtained thus far show a low total mortality--irrespective of cause of death--but a tendency towards an excess risk for cancer morbidity, mainly due to lung cancer.

Humans↗
PubMed1999

[Screening of urogenital malignancies by transabdominal ultrasonography in "human dry dock"].

BACKGROUND: Transabdominal ultrasonography (US) has been widely accepted as a diagnostic method with which to examine multiple organs simultaneously. This study was designed to evaluate the efficacy of trans-abdominal US to screen for urogenital malignancies. METHODS: From 1993 through 1997 109,077 men and 28,023 women underwent abdominal US to screen for abdominal and pelvic diseases as part of a regular health check-up program at the Tokyu Medical Health Center. RESULTS: Twelve renal cell cancers (RCCs), 7 bladder tumors (BTs), 4 prostatic cancers (PCs), and 1 testicular tumor (TT) were detected. All cancers were diagnosed pathologically and treated surgically except for one PC. Surgical pathological examination and conventional imaging revealed that all 12 RCCa and 6 of the 7 BTs were of less advanced stage than pT1N0M0. However, all 3 PCs and the TT were pT3N0-1M0 and pT1N3M0, respectively. The stage and grade of these 12 RCCs were significantly lower than those of 29 symptomatic RCCs. All 12 patients with RCC patients and 6 of the 7 patients with BT had no urological symptom, whereas 3 of the 4 patients with PC and the patient with TT had urogenital symptoms. Microscopic examination of the urine revealed both red blood cells and tumors cells in two of the seven patients with BT. All four patients with PC had serum levels of prostatic-specific antigen greater than 4 ng/ml. CONCLUSION: These results indicate that screening by transabdominal US as part of regular health check-ups can detect many types of urogenital malignancy. In particular, US is useful for detecting low-grade and low-stage RCCs and superficial BTs but is less sensitive for early-stage PCs and TTs.

Adult↗