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At least 1,477 records · Page 82Linked to original sources
PubMed2006

Evaluating scoring functions for docking and designing beta-secretase inhibitors.

Several simple scoring methods were examined for 2 series of beta-secretase (BACE-1) inhibitors to identify a docking/scoring protocol which could be used to design BACE-1 inhibitors in a drug discovery program. Both the PLP1 score and MMFFs interaction energy (E(inter)) performed as well or better than more computationally intensive methods for a set of substrate-based inhibitors, while the latter performed well for both sets of inhibitors.

Amyloid Precursor Protein Secretases↗
PubMed2004

High-throughput docking as a source of novel drug leads.

Receptor-based virtual screening has become a viable source of novel leads in the pharmaceutical industry. The rapidly growing availability of structural information across protein families, the accessibility to increased computational power at affordable cost, as well as an improved understanding on how to effectively apply virtual screening technologies has contributed to their emergence. Nonetheless, continued improvement in the accuracy of scoring functions and a greater understanding of protein mobility is critical to advance the technology further.

Binding Sites↗
PubMed2006

The receptor for branch-site docking within a group II intron active site.

The distinguishing feature of group II introns, and the property that links them with spliceosomal catalysis, is their ability to undergo splicing through branching. In this reaction, the 2'-hydroxyl group of a specific adenosine within intron domain 6 serves as the nucleophile for attack on the 5' splice site. We know less about branching than any other feature of group II intron catalysis, largely because the receptor structure for activating the branch site is unknown. Here, we identify the intronic region that binds the branch site of a group IIB intron. Located in domain 1, close to receptors for intron domain 5 and both splice sites, we demonstrate that the branch-site receptor is a functional element required for transesterification. Furthermore, we show that crosslinked branch sites can carry out both steps of splicing, suggesting that the conformational state of the intron core is set early and that it persists throughout the entire splicing process.

Binding Sites↗
PubMed2004

RIalpha subunit of PKA: a cAMP-free structure reveals a hydrophobic capping mechanism for docking cAMP into site B.

In eukaryotes the primary target for cAMP, a ubiquitous second messenger, is cAMP-dependent protein kinase (PKA). Understanding how binding and release of cAMP changes the cAMP binding domains and then triggers long-range allosteric responses is an important challenge. This conformational switching requires structure solutions of cAMP binding domains in cAMP-bound and cAMP-free states. We describe for the first time a crystal structure of the cAMP binding domains of PKA type Ialpha regulatory subunit where site A is occupied by cGMP and site B is unoccupied. The structure reveals that the carboxyl terminus of domain B serves as a hydrophobic cap, locking the cyclic nucleotide via its adenine ring into the beta-barrel. In the absence of cAMP, the "cap" is released via an extension of the C-terminal helix. This simple hinge mechanism for binding and release of cAMP also provides a mechanism for allosteric communication between sites A and B.

Allosteric Site↗
PubMed2004

Protein-protein interactions; coupling of structurally conserved residues and of hot spots across interfaces. Implications for docking.

Hot spot residues contribute dominantly to protein-protein interactions. Statistically, conserved residues correlate with hot spots, and their occurrence can distinguish between binding sites and the remainder of the protein surface. The hot spot and conservation analyses have been carried out on one side of the interface. Here, we show that both experimental hot spots and conserved residues tend to couple across two-chain interfaces. Intriguingly, the local packing density around both hot spots and conserved residues is higher than expected. We further observe a correlation between local packing density and experimental deltadeltaG. Favorable conserved pairs include Gly coupled with aromatics, charged and polar residues, as well as aromatic residue coupling. Remarkably, charged residue couples are underrepresented. Overall, protein-protein interactions appear to consist of regions of high and low packing density, with the hot spots organized in the former. The high local packing density in binding interfaces is reminiscent of protein cores.

Alanine↗
PubMed2006

Mitochondrial DNA clonality in the dock: can surveillance swing the case?

Mitochondrial DNA (mtDNA) is a favoured tool of evolutionary biologists because its high mutation rate generates enough signal to make inferences about population history over short time frames. Furthermore, mtDNA inheritance is clonal, being transmitted only through the maternal line. This enables evolutionary histories to be assembled without the complexities introduced by biparental recombination. Recently, a single case of human biparental inheritance has been reported. Given this, and the role supposed clonal inheritance has had in shaping our knowledge of human population history, it is essential to establish a method for identifying any recombinant mtDNA molecules in our population. A reliable surveillance mechanism would either maintain our confidence in clonal inheritance or indicate the inaccuracy of our inferences.

DNA, Mitochondrial↗
PubMed2000

William Dock, MD.

Explore the source record for details and available documents.

Ballistocardiography↗
PubMed1993

Single event recording shows that docking onto receptor alters the kinetics of membrane fusion mediated by influenza hemagglutinin.

The initial steps of membrane fusion, receptor binding and membrane destabilization, are mediated by the envelope glycoprotein hemagglutinin of influenza virus. Interaction between these functions was determined from the time course of individual virion fusions to a planar membrane with and without receptor. With receptor, fusion was described by a Poisson process. In the absence of receptor, the time course was more complicated and could not be described with exponential rate constants. The conversion of a non-Markovian process into a simple Markov chain is direct evidence that receptor binding fundamentally alters the route of fusion.

Binding Sites↗
PubMed2003

Requirement of autophosphorylated tyrosine 992 of EGF receptor and its docking protein phospholipase C gamma 1 for membrane ruffle formation.

Stimulation of the epidermal growth factor receptor (EGFR) produces membrane ruffles through the small G protein Rac1; however, the signaling pathway from EGFR to Rac1 has not yet been clarified. Here, we show that autophosphorylation of EGFR at tyrosine 992 is required for EGF-induced membrane ruffle formation in CHO cells. Signaling from the autophosphorylated tyrosine 992 appears to be mediated by phospholipase C (PLC) gamma 1. Furthermore, activation of Rac1 by EGF is inhibited by a PLC inhibitor. These results, taken together, suggest that autophosphorylation of EGFR at tyrosine 992 and the subsequent PLC gamma 1 activation transduce the signal to Rac1 to induce membrane ruffle formation.

Animals↗
PubMed1996

Amino acids of the alpha1B-adrenergic receptor involved in agonist binding: differences in docking catecholamines to receptor subtypes.

Site-directed mutagenesis and molecular dynamics analysis of the 3-D model of the alpha1B-adrenergic receptor (AR) were combined to identify the molecular determinants of the receptor involved in catecholamine binding. Our results indicate that the three conserved serines in the fifth transmembrane domain (TMD) of the alpha1B-AR play a distinct role in catecholamine binding versus receptor activation. In addition to the amino acids D125 in TMDIII and S207 in TMDV directly involved in ligand binding, our findings identify a large number of polar residues playing an important role in the activation process of the alpha1B-AR thus providing new insights into the structure/function relationship of G protein-coupled receptors.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1986

The catalytic mechanism of serine proteases. III. An Indo-ISCRF study of the methylacetate docking in alpha-chymotrypsin.

Mechanistic steps of the catalytic hydrolysis of methylacetate by alpha-chymotrypsin have been studied with the inhomogeneous selfconsistent reaction field theory of protein core effects. Protein-substrate interactions were optimized at each step of the reaction path by using the REFINE program. The state of charge of the acid and basic side chains together with the amino terminal group have been used to mimic pH effects. The experimental facts concerning the catalytic activity are fairly well reproduced in our simulations. In particular, the trends in activation barrier as a function of pH are good, although the actual energetic barriers are much too large.

Acetates↗
PubMed2003

Pox in the docks: varicella outbreak in an Australian prison system.

OBJECTIVES: 1. Describe an outbreak of varicella in a prison system. 2. Highlight the risks of disease transmission within the prison environment. 3. Promote infection control guidelines for high-risk sub-groups within the prison system, including the application of quarantine. SETTING: Four prisons, one prison hospital, the prison transport system, one courthouse. MAIN OUTCOME MEASURES: Number of cases of varicella infection; reported varicella immunity status of cases and contacts; immunity status of known HIV antibody positive inmates. RESULTS: Five cases of chickenpox were identified. There were 23 contacts of the Index Case occurring during transport between prison and court and whilst being held in the court holding cells. Two of these contacts developed chickenpox despite having given a prior history of infection. There were over 300 inmates exposed to varicella zoster virus (VZV) during the outbreak, including one HIV antibody positive inmate who had serologically confirmed immunity. This inmate developed shingles following exposure to VZV from one of the cases. CONCLUSIONS: There is an elevated risk of respiratory transmission of infections such as chickenpox in prisons. Clear guidelines should be in place to protect HIV antibody positive people, pregnant women, and others who are at increased risk of complications from such infections. In the case of varicella, all inmates and staff without documented immunity should be screened to determine immunity, and if non-immune, should be offered VZV vaccination. Every effort should be made to prevent HIV antibody positive inmates being exposed to varicella, regardless of their varicella immunity status. If an HIV antibody positive inmate, who is known to be non-immune is exposed to varicella, Varicella Zoster immunoglobulin should be given within 96 h.

Adult↗