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At least 1,405 records · Page 78Linked to original sources
PubMed2000

The ShcA phosphotyrosine docking protein sensitizes cardiovascular signaling in the mouse embryo.

The ShcA gene products have served as a model for the analysis of phosphotyrosine-recognition domains, and for the functions of docking proteins during tyrosine kinase signaling. Here we show that ShcA is primarily expressed in the cardiovascular system during early mouse embryogenesis and regulates both heart development and establishment of mature blood vessels. Targeted mutation suggests that the ShcA adaptor is a pivotal target of tyrosine kinases that selectively potentiates activation of the MAP kinase pathway in the remodeling vasculature. Biochemical analysis of mutant cells shows that ShcA sensitizes cells to growth factor-induced MAP kinase activation, and also organizes cytoskeletal rearrangement in response to the extracellular matrix. ShcA may therefore orchestrate complex interactions within the vascular compartment by rendering cells permissive to respond to soluble and adhesive external cues.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Theoretical evidence of a salt bridge disruption as the initiating process for the alpha1d-adrenergic receptor activation: a molecular dynamics and docking study.

This study reports the building of the three-dimensional structure of the rat alpha1d-adrenergic receptor through a topology approach based on the structure of the rhodopsin receptor from cryoelectron microscopy. The validity and reliability of the receptor model were assessed through exhaustive molecular dynamics and docking studies. Some interesting ligand-receptor interactions were identified along with significant differences between the binding mode of agonists and antagonists. The importance of the disruption of a salt bridge as a possible initial event leading to receptor activation is discussed on the basis of data from mutagenesis and molecular dynamics studies.

Amino Acid Sequence↗
PubMed1975

Prevention of decompression sickness during a simulated space docking mission.

This study has shown that repetitive exchanges between the American Apollo space vehicle atmosphere of 100% oxygen at 5 psia (258 torr) and the Russian Soyuz spacecraft atmosphere of 30% oxygen-70% nitrogen at 10 psia (523 torr), as simulated in altitude chambers, will not likely result in any form of decompression sickness. This conclusion is based upon the absence of any form of bends in seven crewmen who participated in 11 tests distributed over three 24-h periods. During each period, three transfers from the 5 to the 10 psia environments were performed by simulating passage through a docking module which served as an airlock where astronauts and cosmonauts first adapted to each other's cabin gases and pressures before transfer. Biochemical tests, subjective fatigue scores, and the complete absence of any form of pain were also indicative that decompression sickness should not be expected if this spacecraft transfer schedule is followed.

17-Hydroxycorticosteroids↗
PubMed2000

MIAX: a system for assessment of macromolecular interaction. 3) A parallel hybrid GA for flexible protein docking.

We propose a parallel hybrid genetic algorithm for flexible protein-protein docking in order to improve the conventional rigid-body models to manipulate protein-protein interactions. The proposed hybrid algorithm is a combination of an evolutionary algorithm with a simulated annealing one, yielding a powerful protein-complex conformation-searching engine. Parallelization of the procedure makes possible to reach high algorithm performance, in both, execution times and size of treated monomers and complexes. Knowledge on side chain flexibility is extracted by means of an exhaustive analysis of crystallographic data on proteins and protein complexes. Results demonstrate the competency of the algorithm since comparison of calculated and crystallographic data accounts for a maximum of 2.5A in RMS difference, including side chain conformation. The system allows routine analysis of this fundamental molecular biology problem important to elucidate bio-macromolecular function in biophysical and biochemical mechanisms involving molecular recognition and interaction, yielding simultaneously clues for designing new proteins and enzymes directed to different purposes.

Algorithms↗
PubMed1998

Flexible Docking of Proteins and "Drug-like" Ligands.

By using "tabu search" algorithm and Gehlhaar potential function, a new approach is presented for flexible docking of protein and its "drug-like" ligand has been developed. Computational test for this method with a set of 100 complexes has been performed, which indicated that the deviation of 89% of the predicted complex conformation was less than 0.25 nm. Compared with GOLD, a program of genetic algorithm, our method has high accuracy, low limit and short computation time.

Journal Article↗
PubMed2001

[Studied on docking of 5,6-diaryl-2,3-dihydro-1-pyrrolizinone derivatives with cyclooxygenase].

AIM: To theoretically explore the mechanism of action of 5,6-diaryl-2, 3-dihydro-1-pyrrolizinone derivatives. METHODS: The interactions of the compound ZZ-122 with cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were modeled by docking method. RESULTS: According to the binding pattern, intermolecular energy and capacity to form H-bond, it was easy for ZZ-122 to bind to COX-2 and not easy to COX-1. CONCLUSION: Compound ZZ-122 may be a selective COX-2 inhibitor, which has to be confirmed by experiment.

Cyclooxygenase 1↗
PubMed2003

[Analysis of dot-like hemosiderin spots using brain dock system].

BACKGROUND AND PURPOSE: Dot-like low intensity spots (a dot-like hemosiderin spot: dotHS) on T2*-weighted MR images (T2*WI), which is regarded as a sensitive method for hemosiderin detection, have been histologically diagnosed as old microbleeds associated with microangiopathies. The clinical significance of the dotHS, however, is still under debate. Therefore, we investigated the factors associated with dotHS. METHODS: We investigated 209 healthy volunteers in our hospital (sex: 106 males, 103 females; age: 38 to 78 years old, mean age: 56.4 +/- 8.3 years old) using "Brain Dock", a formalized screening system for asymptomatic brain diseases. The Odds ratio (OR) was estimated from multiple logistic regression analyses using the dotHS and variables. RESULTS: T2*WI demonstrated dotHS in 7.7% of volunteers, and the mean number of dotHS was 0.16 +/- 0.78. The hemosiderin was preferentially deposited in the basal ganglia and thalamus. Age > or = 65 years old (OR: 5.9; 95% confidence interval [CI]: 1.4-25.9; p = 0.02), hypertension (OR: 7.0; 95% CI: 1.4-34.7; p = 0.02), and headache (OR: 5.8; 95% CI: 1.4-24.6; p = 0.02) were all found to be independently associated with dotHS. CONCLUSIONS: The dotHS was significantly associated with several factors, including age, hypertension and headache.

Adult↗
PubMed2003

Structure activity relationship studies of cinnamic acid derivatives as inhibitors of human neutrophil elastase revealed by ligand docking calculations.

Structure-activity relationship of cinnamic acid derivatives as inhibitors of the human neutrophil elastase is reported. Comparison of the inhibitory concentrations (IC50 values) with the results of the ligand docking calculations revealed that the structure element of the aromatic ortho-dihydroxy groups combined with a lipophilic residue seems to be a prerequisite for an optimal binding within the active site.

Cimicifuga↗
PubMed2003

Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (irinotecan, CPT-11) is a camptothecin prodrug that is metabolized by carboxylesterases (CE) to the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), a topoisomerase I inhibitor. CPT-11 has shown encouraging antitumor activity against a broad spectrum of tumor types in early clinical trials, but hematopoietic and gastrointestinal toxicity limit its administration. To increase the therapeutic index of CPT-11 and to develop other prodrug analogues for enzyme/prodrug gene therapy applications, our laboratories propose to develop camptothecin prodrugs that will be activated by specific CEs. Specific analogues might then be predicted to be activated, for example, predominantly by human liver CE(hCE1), by human intestinal CE (hiCE), or in gene therapy approaches using a rabbit liver CE (rCE). This study describes a molecular modeling approach to relate the structure of rCE-activated camptothecin prodrugs with their biological activation. Comparative molecular field analysis, comparative molecular similarity index analysis, and docking studies were used to predict the biological activity of a 4-benzylpiperazine derivative of CPT-11 [7-ethyl-10-[4-(1-benzyl)-1-piperazino]carbonyloxycamptothecin (BP-CPT)] in U373MG glioma cell lines transfected with plasmids encoding rCE or hiCE. BP-CPT has been reported to be activated more efficiently than CPT-11 by a rat serum esterase activity; however, three-dimensional quantitative structure-activity relationship studies predicted that rCE would activate BP-CPT less efficiently than CPT-11. This was confirmed by both growth inhibition experiments and kinetic studies. The method is being used to design camptothecin prodrugs predicted to be activated by specific CEs.

Animals↗
PubMed2005

A mutation in the common docking domain of ERK2 in a human cancer cell line, which was associated with its constitutive phosphorylation.

The EGFR/Ras/Raf/MEK/ERK pathway is a major pathway involved in the control of growth signals, cell survival and differentiation. Mutations of signaling components, such as EGFR (c-erbB1), Ras, and B-Raf, have been shown to play roles in the genesis of human cancer, while point mutation of ERK has not been reported. In this study, we present evidence for a mutation in an oral squamous cell carcinoma cell line, HSC6. PCR-amplification of cDNA, cloning and sequencing resulted in the identification of glutamic acid to lysine substitution at codon 322 (E322K) that occurred in the common docking (CD) domain of ERK2. The mutant protein contributed towards faster-migration in SDS-PAGE, and constitutive phosphorylation in a MEK-dependent manner. The transient transfection of the mutant ERK2 in 293T cells resulted in the expression of the same faster-migrating band in SDS-PAGE as was detected in HSC6 cells, which was preferentially phosphorylated relative to endogenous wild-type ERK2. The present study is the first to report ERK2 substitution mutation in a human cancer cell line which resulted in constitutive phosphorylation.

Amino Acid Sequence↗
PubMedDate not supplied

[Refining the structure of the strongly bound actin-myosin complex by protein docking].

The structure of the strongly bound complex of the globular myosin head and F-actin is a key for understanding some important details of the mechanism of the actin-myosin motor. Current knowledge about the structure is based on the docking of known atomic structures of actin and myosin heads into low-resolution EM electron density maps. To refine the structure, we suggested a new approach based on energy minimization using the ICM-Pro software. The minimization includes rigid-body movement of protein backbone and side chain optimization on the protein interface. Our best model structure is similar to that obtained from EM. It also provides the highest calculated interaction energy and agrees with a number of mutagenesis experiments. Using the structure, we suggest molecular explanations for actin activation of product release from myosin and actin-induced myosin dissociation.

Actins↗
PubMed2006

[Prohibition to exhibit docked dogs--problems of execution].

In Germany it is illegal to exhibit dogs when parts of their body are amputated to meet certain distinctions of their race except there has been a medical reason for the operation. Experiences in practice with the inspection of dog exhibitions reveal that this exceptional rule is not effective. Many breeders and owners of dogs, especially of the race "Doberman", try to escape the prohibition to exhibit docked dogs with the help of dubious veterinarian certificates. Therefore it is proposed to eliminate this exception from section 10 of the regulation on the welfare of dogs.

Animal Welfare↗
PubMed1990

Fatal poisoning by Rumex crispus (curled dock): pathological findings and application of scanning electron microscopy.

A case of fatal poisoning due to ingestion of the plant Rumex crispus (curled dock) is described. The patient, a 53-year-old male, presented with gastrointestinal symptoms, severe hypocalcemia, metabolic acidosis and acute hepatic insufficiency. Despite therapeutic measures, the patient died 72 h after ingestion of the plant material. Noteworthy among the pathological findings were centrolobular hepatic necrosis and birefringent crystals in the liver and kidneys that were identified by histochemical techniques and scanning electron microscopy. These observations are compared with other reports in the medical literature, with an emphasis on the risk involved in the use of these plants for culinary or medicinal purposes.

Edema↗
PubMed1990

Acute oxalate poisoning attributable to ingestion of curly dock (Rumex crispus) in sheep.

Ten of 100 mature ewes were afflicted with acute oxalate toxicosis within 40 hours after being temporarily penned in a lot that contained considerable growing Rumex crispus (curly dock). Clinical signs of toxicosis included excess salivation, tremors, ataxia, and recumbency. Affected ewes were markedly hypocalcemic and azotemic. Oxalate crystals were not observed in urine. Gross postmortem lesions were minimal and nondiagnostic in 2 ewes that died peracutely, but perirenal edema and renal tubular degeneration were clearly observable in ewes euthanatized on the third day of toxicosis. Diagnosis of oxalate toxicosis was confirmed by histopathologic findings. Samples of Rumex spp contained 6.6 to 11.1% oxalic acid on a dry-weight basis, a concentration comparable with that in other oxalate-containing plants that have caused acute oxalate toxicosis.

Acute Kidney Injury↗
PubMed1985

Docking of cyclohexanol-derivatives into the active site of liver alcohol dehydrogenase. Using computer graphics and energy minimization.

Model building and energy minimization procedures have been used to determine a productive substrate binding mode in liver alcohol dehydrogenase for secondary alcohols. These docking results have been compared to some of the extensive amounts of kinetic data available for this enzyme. The indirect diamond lattice approach first suggested by Prelog (Prelog, V. (1964) Pure Appl. Chem. 9, 119-130) to describe the active site of an enzyme has been used to build a direct diamond lattice from the crystallographic model of the enzyme. This lattice was oriented and positioned into the active site using the productive binding mode of cyclohexanol derivatives obtained from model building. We then classified the positions as allowed, forbidden, or boundary depending on their distances to protein atoms. We found very good agreement between the classification of our direct diamond lattice points and those of the indirect lattice obtained by others from kinetic studies. Finally we have extended the lattice as an aid to predict the stereospecificity of the enzyme for molecules which cover other regions of the active site.

Alcohol Dehydrogenase↗
PubMed1995

Protein docking combining symbolic descriptions of molecular surfaces and grid-based scoring functions.

With the growing number of known 3D protein structures, computing systems, that can predict where two protein molecules interact with each other is becoming of increasing interest. A system is presented, integrating preprocessing like the computation of molecular surfaces, segmentation, and searching for complementarity in the general framework of a pattern analyzing semantic network (ERNEST). The score of coarse symbolic computations is used by the problem independent control strategy of ERNEST to guide a more detailed analysis considering steric clash and judgements based on grid-based surface representations. Successful examples of the docking system are discussed that compare well with other approaches.

Binding Sites↗
PubMed1993

Diesel exhaust exposure and smoking: a case-referent study of lung cancer among Swedish dock workers.

We studied 50 lung cancer cases and 154 matched referents, all dock workers, for whom we obtained smoking information and employment histories. We assessed exposures from information on annual diesel fuel consumption from each of the 15 ports included. We used a smoker/nonsmoker term and three exposure variables (machine time, cumulative fuel, and exposed time with fuel consumption above a minimum cutpoint) in the analyses, with three categories for each exposure variable. Odds ratios (ORs) for medium and high exposure groups are consistently higher than reference (low), with an increasing exposure-response trend that is most marked for the exposed time variable (ORs: low = 1.0; medium = 1.6; high = 2.8). When smoking and that exposure variable are simultaneously included in the analyses, odds ratios for the medium (OR = 2.7) and high (OR = 6.8) levels of exposure increase, as does the odds ratio for smoking. Separating smokers and nonsmokers, with the low exposed nonsmokers as the common reference category, the odds ratios are 1.6 (medium) and 2.9 (high) for the nonsmokers, and 10.7 (medium) and 28.9 (high) for smokers. These results indicate an independent effect of diesel exhaust exposure and a strong interaction between smoking and diesel exhaust.

Humans↗