A5000978218- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Cell Adhesion Molecules Research
- Pharmacological Receptor Mechanisms and Effects
- Computational Drug Discovery Methods
- Platelet Disorders and Treatments
- Lipid Membrane Structure and Behavior
- Neuroscience and Neuropharmacology Research
- Mass Spectrometry Techniques and Applications
- Protein Structure and Dynamics
- Monoclonal and Polyclonal Antibodies Research
- Chemical Synthesis and Analysis
- Photoreceptor and optogenetics research
- Pharmacological Effects and Assays
- Ion channel regulation and function
- Biochemical and Structural Characterization
- Blood disorders and treatments
- Nicotinic Acetylcholine Receptors Study
- Protein Kinase Regulation and GTPase Signaling
- Chemical synthesis and alkaloids
- Lymphoma Diagnosis and Treatment
- Heparin-Induced Thrombocytopenia and Thrombosis
- Ion Channels and Receptors
- Alkaloids: synthesis and pharmacology
- Glycosylation and Glycoproteins Research
Icahn School of Medicine at Mount Sinai
2016-2025
New York Proton Center
2023
Cornell University
2004-2021
Weill Cornell Medicine
2021
Mount Sinai Hospital
2009-2015
National Center for Advancing Translational Sciences
2014
Rockefeller University
2014
National Institutes of Health
2014
Abcam (United States)
2014
Columbia University Irving Medical Center
2014
Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there a longstanding interest in development new opioid analgesics improved profiles. The alkaloids Southeast Asian plant Mitragyna speciosa, represented by prototypical member mitragynine, are an unusual class modulators distinct pharmacological properties. Here we describe...
G protein-coupled receptors (GPCRs) constitute a functionally diverse protein family and are targets for broad spectrum of pharmaceuticals. Technological progress in X-ray crystallography cryogenic electron microscopy has enabled extensive, high-resolution structural characterisation GPCRs different conformational states. However, as highly dynamic events underlie GPCR signalling, complete understanding functionality requires insights into their dynamics. Here, we present large dataset...
Functional crosstalk between G protein-coupled receptors in a homo- or heterodimeric assembly likely involves conformational changes at the dimer interface, but nature of this interface is not yet established, and dynamic have been identified. We mapped homodimer dopamine D2 receptor over entire length fourth transmembrane segment (TM4) by crosslinking substituted cysteines. Their susceptibilities to are differentially altered presence agonists inverse agonists. The TM4 agonist-bound...
The recent availability in the literature of new crystal structures inactive G-protein coupled receptors (GPCRs) prompted us to study extent which these constitute an advantage over former prototypic rhodopsin template for homology modeling transmembrane (TM) region human class A GPCRs. Our results suggest that better templates than those currently available are required by majority GPCRs generate models accurate enough simple virtual screening aimed at computer-aided drug discovery. Thus,...
G protein-coupled receptors play a pivotal role in many physiological signaling pathways. Mounting evidence suggests that receptors, including opioid form dimers, and dimerization is necessary for receptor maturation, signaling, trafficking. However, the of vivo has not been well-explored because lack tools to study these dimers endogenous systems. To address this problem, we previously generated antibodies μ-δ (μOR-δOR) used them pharmacology by heteromer. We also showed heteromer exhibits...
Spatial organization of G-protein coupled receptors (GPCRs) into dimers and higher order oligomers has been demonstrated in vitro vivo. The pharmacological readout was shown to depend on the specific interfaces, but why particular regions GPCR structure are involved how ligand-determined states change them remains unknown. Here we show protein-membrane hydrophobic matching is attained upon oligomerization at interfaces from an analysis coarse-grained molecular dynamics simulations...
YiiP is a dimeric Zn 2+ /H + antiporter from Escherichia coli belonging to the cation diffusion facilitator family. We used cryoelectron microscopy determine 13-Å resolution structure of homolog Shewanella oneidensis within lipid bilayer in absence . Starting X-ray presence , we molecular dynamics flexible fitting build model consistent with our map. Comparison structures suggests conformational change that involves pivoting transmembrane, four-helix bundle (M1, M2, M4, and M5) relative...
The idea of sodium ions altering G-protein-coupled receptor (GPCR) ligand binding and signaling was first suggested for opioid receptors (ORs) in the 1970s subsequently extended to other GPCRs. Recently published ultra-high-resolution crystal structures GPCRs, including that δ-OR subtype, have started shed light on mechanism underlying control GPCR by revealing details site. Whether accesses different subtypes from extra- or intracellular sides, following similar pathways, is still an open...
Substantial attention has recently been devoted to G protein-biased agonism of the μ-opioid receptor (MOR) as an ideal new mechanism for design analgesics devoid serious side effects. However, designing opioids with appropriate efficacy and bias is challenging because it requires understanding ligand binding process allosteric modulation receptor. Here, we investigated these phenomena TRV-130, a MOR small-molecule agonist that shown exert analgesia less respiratory depression constipation...
Considerable evidence has accumulated in recent years suggesting that G protein-coupled receptors (GPCRs) associate the plasma membrane to form homo- and/or heteromers. Nevertheless, stoichiometry, fraction and lifetime of such receptor complexes living cells remain topics intense debate. Motivated by experimental data differing stabilities for homomers cognate human β1- β2-adrenergic receptors, we have carried out approximately 160 microseconds biased molecular dynamics simulations...
Extensive experimental information supports the formation of ligand-specific conformations G protein-coupled receptors (GPCRs) as a possible molecular basis for their functional selectivity signaling pathways. Taking advantage recently published inactive and active crystal structures GPCRs, we have implemented an all-atom computational strategy that combines different adaptive biasing techniques to identify along pre-determined activation Using prototypic GPCR β2-adrenergic receptor suitable...
A new drug blocks platelet aggregation by interacting with the integrin receptor differently from current drugs that cause adverse side effects.
Available crystal structures of opioid receptors provide a high-resolution picture ligand binding at the primary ("orthosteric") site, that is, site targeted by endogenous ligands. Recently, positive allosteric modulators have also been discovered, but their modes and action remain unknown. Here, we use metadynamics-based strategy to efficiently sample process recently discovered modulator δ-opioid receptor, BMS-986187, in presence orthosteric agonist SNC-80, with receptor embedded an...
Treatment of myocardial infarction within the first 1 to 2 hours with a thrombolytic agent, percutaneous coronary intervention, or an αIIbβ3 antagonist decreases mortality and later development heart failure. We previously reported on novel small molecule antagonist, RUC-2, that has unique mechanism action. have now developed more potent soluble congener RUC-4, designed be easily administered intramuscularly by autoinjector facilitate its use in prehospital setting. Here, we report...