A5068132019- Lipid Membrane Structure and Behavior
- Sphingolipid Metabolism and Signaling
- Receptor Mechanisms and Signaling
- Parkinson's Disease Mechanisms and Treatments
- Supramolecular Self-Assembly in Materials
- Antimicrobial Peptides and Activities
- Alzheimer's disease research and treatments
- Cellular transport and secretion
- Neurological disorders and treatments
- Erythrocyte Function and Pathophysiology
- Spectroscopy and Quantum Chemical Studies
- Wnt/β-catenin signaling in development and cancer
- Lysosomal Storage Disorders Research
- Inhalation and Respiratory Drug Delivery
- Neuroinflammation and Neurodegeneration Mechanisms
- Histone Deacetylase Inhibitors Research
- Chemokine receptors and signaling
- Photoreceptor and optogenetics research
- Biotin and Related Studies
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Drug Transport and Resistance Mechanisms
- Immune cells in cancer
- Inflammasome and immune disorders
- Protein Degradation and Inhibitors
- Endoplasmic Reticulum Stress and Disease
Scripps Research Institute
2005-2012
Screen
2008
La Jolla Institute for Immunology
2004
Queen's University
2002
University of Toronto
1994-2001
Hospital for Sick Children
1994-2001
Ohio University
1998
SickKids Foundation
1997
The lyso-phospholipid sphingosine 1-phosphate modulates lymphocyte trafficking, endothelial development and integrity, heart rate, vascular tone maturation by activating G protein-coupled receptors. Here, we present the crystal structure of receptor 1 fused to T4-lysozyme (S1P(1)-T4L) in complex with an antagonist sphingolipid mimic. Extracellular access binding pocket is occluded amino terminus extracellular loops receptor. Access gained ligands entering laterally between helices I VII...
Sphingosine 1-phosphate (S1P) influences heart rate, coronary artery caliber, endothelial integrity, and lymphocyte recirculation through five related high affinity G-protein-coupled receptors. Inhibition of by non-selective S1P receptor agonists produces clinical immunosuppression preventing transplant rejection but is associated with transient bradycardia. Understanding the contribution individual receptors has been limited embryonic lethality S1P(1) knock-out unavailability selective or...
With the discovery of missense mutations (A53T and A30P) in α-synuclein (α-Syn) several families with early onset familial Parkinson's disease, α-Syn aggregation fibril formation have been thought to play a role pathogenesis α-synucleinopathies, such as dementia Lewy bodies, multiple system atrophy. As previous reports suggested that plays lipid transport synaptic membrane biogenesis, we investigated whether binds specific ligand using thin layer chromatography overlay examined changes its...
Pulmonary pathologies including adult respiratory distress syndrome are characterized by disruption of pulmonary integrity and edema compromising function. Sphingosine 1-phosphate (S1P) is a lipid mediator synthesized and/or stored in mast cells, platelets, epithelial with production up-regulated the proinflammatory cytokines IL-1 TNF. S1P administration via airways but not vasculature induces lung leakage. Using receptor-null mice, we show that S1P, acting on S1P3 receptor expressed both...
Strong evidence exists for interactions of zwitterionic phosphate and amine groups in sphingosine-1 (S1P) to conserved Arg Glu residues present at the extracellular face third transmembrane domain S1P receptors. The contribution Arg<sup>120</sup> Glu<sup>121</sup> high-affinity ligand-receptor is essential, because single-point R<sup>120</sup>A or E<sup>121</sup>A S1P<sub>1</sub> mutants neither bind nor transduce function. Because receptors are therapeutically interesting, identifying...
Sphingosine 1-phosphate (S1P) is a lysophospholipid signaling molecule that regulates important biological functions, including lymphocyte trafficking and vascular development, by activating G protein-coupled receptors for S1P, namely, S1P(1) through S1P(5). Here, we map the S1P(3) binding pocket with novel allosteric agonist (CYM-5541), an orthosteric (S1P), bitopic antagonist (SPM-242). With combination of site-directed mutagenesis, ligand competition assay, molecular modeling, concluded...
alpha-Synuclein exists in two different compartments vivo-- correspondingly existing as forms: a membrane-bound form that is predominantly alpha-helical and cytosolic randomly structured. It has been suggested these environmental structural differences may play role aggregation propensity development of pathological lesions observed Parkinson's disease (PD). Such effects be accentuated by mutations familial PD kindreds. In order to test this hypothesis, wild-type A53T mutant alpha-synuclein...
When isolated from central nervous system myelin, myelin basic protein (MBP) exhibits charge microheterogeneity due to posttranslational deamidation, phosphorylation, and deimination of arginine citrulline. These modifications are known decrease the ability MBP aggregate acidic lipid vesicles thus could regulate mediate adhesion between intracellular surfaces myelin. The effects salt (KCl) concentration ratio on isomers large unilamellar (LUVs) were investigated. Increased 10 100 mM caused...
We have studied the sphingosine 1-phosphate (S1P) receptor system to better understand why certain molecular targets within a closely related family are much more tractable when identifying compelling chemical leads. Five medically important G-protein-coupled receptors for S1P regulate heart rate, coronary artery caliber, endothelial barrier integrity, and lymphocyte trafficking. Selective agonist probes would be of great utility study subtype-specific function. Through systematic screening...
In the compacted multilayered myelin sheath of central nervous system, basic protein (MBP) is thought to be responsible for adhesion intracellular surfaces by electrostatic interactions with acidic lipids. Noncompacted regions containing cytosol exist and can take up potassium released into extracellular fluid after axonal action potential. Therefore, effect K+ concentration on ability MBP aggregate large unilamellar vesicles (LUVs) phosphatidylcholine (PC) 10-20% lipid was investigated. At...
We investigated the interaction of antimicrobial peptides Ala19-magainin 2 amide and magainin with lipid using two photolabels, azidobenzoyl galactosylceramide (GalCer-PL) azidobenzoylamido capryloyl (GalCer-C8-PL), which position their photosensitive groups near apolar−polar interface center bilayer, respectively. Magainins have been postulated to permeabilize membranes either by inserting in a transmembrane fashion into bilayer forming channel or binding surface disturbing packing....
(1) Background: An important concomitant of stroke is neuroinflammation. Pomalidomide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers TNF-α generation and thus has potent anti-inflammatory actions. Well-tolerated analogs may provide treatment allow evaluation the role neuroinflammation ischemic brain. (2) Methods: Two novel pomalidomide derivatives, 3,6′-dithiopomalidomide (3,6′-DP) 1,6′-dithiopomalidomide (1,6′-DP), were evaluated alongside rat...