Functional validation of virtual screening for novel agents with general anesthetic action at ligand-gated ion channels.

GABA(A) receptors play a crucial role in the actions of general anesthetics. The recently published crystal structure of the general anesthetic propofol bound to Gloeobacter violaceus ligand-gated ion channel (GLIC), a bacterial homolog of GABA(A) receptors, provided an opportunity to explore structure-based ligand discovery for pentameric ligand-gated ion channels (pLGICs). We used molecular docking of 153,000 commercially available compounds to identify molecules that interact with the propofol binding site in GLIC.

Molecular mechanism for the dual alcohol modulation of Cys-loop receptors.

Cys-loop receptors constitute a superfamily of pentameric ligand-gated ion channels (pLGICs), including receptors for acetylcholine, serotonin, glycine and γ-aminobutyric acid. Several bacterial homologues have been identified that are excellent models for understanding allosteric binding of alcohols and anesthetics in human Cys-loop receptors. Recently, we showed that a single point mutation on a prokaryotic homologue (GLIC) could transform it from a channel weakly potentiated by ethanol into a highly ethanol-sensitive channel.

Molecular analysis of the membrane insertion domain of proteinase 3, the Wegener's autoantigen, in RBL cells: implication for its pathogenic activity.

PR3, also called myeloblastin, is a neutrophil serine protease that promotes myeloid cell proliferation by cleaving the cyclin-dependent kinase inhibitor p21(cip1/waf1). In addition, it is the target of ANCA in GPA, a necrotizing vasculitis. Anti-PR3 ANCA binding to membrane-expressed PR3 triggers neutrophil activation, potentiating vascular inflammation.

Molecular dynamics simulations of mixed acidic/zwitterionic phospholipid bilayers.

Anionic lipids are key components in the cell membranes. Many cell-regulatory and signaling mechanisms depend upon a complicated interplay between them and membrane-bound proteins. Phospholipid bilayers are commonly used as model systems in experimental or theoretical studies to gain insight into the structure and dynamics of biological membranes.

How does proteinase 3 interact with lipid bilayers?

Proteinase 3 (PR3) is a serine protease of the neutrophils whose membrane expression is relevant in a number of inflammatory pathologies. It has been shown to strongly interact with reconstituted bilayers containing dimyristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG) or mixtures of both phospholipids. Here we present the results of molecular dynamics simulations of PR3 anchored at three different phospholipid bilayers: DMPC, DMPG and an equimolar mixture of DMPC/DMPG.

Structures of human proteinase 3 and neutrophil elastase--so similar yet so different.

Proteinase 3 and neutrophil elastase are serine proteinases of the polymorphonuclear neutrophils, which are considered to have both similar localization and ligand specificity because of their high sequence similarity. However, recent studies indicate that they might have different and yet complementary physiologic roles. Specifically, proteinase 3 has intracellular specific protein substrates resulting in its involvement in the regulation of intracellular functions such as proliferation or apoptosis.