A5009029370- Lipid Membrane Structure and Behavior
- Protein Structure and Dynamics
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- RNA and protein synthesis mechanisms
- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Bacterial Genetics and Biotechnology
- Heat shock proteins research
- Vibrio bacteria research studies
- Photoreceptor and optogenetics research
- Neuropeptides and Animal Physiology
- RNA Interference and Gene Delivery
- Nanopore and Nanochannel Transport Studies
- Mass Spectrometry Techniques and Applications
- Enzyme Structure and Function
- Solid-state spectroscopy and crystallography
- bioluminescence and chemiluminescence research
- Advanced Chemical Physics Studies
- Computational Drug Discovery Methods
- Endoplasmic Reticulum Stress and Disease
- Spectroscopy and Quantum Chemical Studies
- Inflammatory mediators and NSAID effects
- Renin-Angiotensin System Studies
- Electrochemical Analysis and Applications
Weill Cornell Medicine
2022-2025
Cornell University
2022-2025
Johns Hopkins University
2017-2024
University of Iowa
2012-2021
Baylor College of Medicine
2008
Max Planck Institute for Chemistry
1991
Johannes Gutenberg University Mainz
1991
Transmembrane β-barrel proteins (TMBs) are of great interest for single-molecule analytical technologies because they can spontaneously fold and insert into membranes form stable pores, but the range pore properties that be achieved by repurposing natural TMBs is limited. We leverage power de novo computational design coupled with a "hypothesis, design, test" approach to determine TMB principles, notably, importance negative slow β-sheet assembly. new eight-stranded TMBs, no homology known...
The metabotropic glutamate receptors (mGluRs) are family C, dimeric G protein–coupled (GPCRs), which play critical roles in synaptic transmission. Despite an increasing appreciation of the molecular diversity this family, how distinct mGluR subtypes regulated remains poorly understood. We reveal that different group II/III show markedly beta-arrestin (β-arr) coupling and endocytic trafficking. While mGluR2 is resistant to internalization mGluR3 shows transient β-arr coupling, enables...
The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane (TMDs) drive intracellular signaling. Pharmacologically, mGluRs can be targeted at the LBDs by synthetic orthosteric compounds or TMDs allosteric modulators. Despite potential of therapeutics, an understanding functional structural basis their effects is limited. Here we use multiple...
Abstract Despite the widespread physiological roles of beta-arrestin (β-arr) coupling in G protein-coupled receptor (GPCR) regulation, molecular basis GPCR/β-arr interaction has been studied primarily monomeric family A GPCRs. Here we take an integrative biophysical and structural approach to uncover extreme diversity β-arr neuromodulatory metabotropic glutamate receptors (mGluRs), prototypical, dimeric C Using a new single molecule pulldown assay, find that mGluRs couple β-arrs with 2:1 or...
Significance Outer membrane proteins play critical roles in bacterial physiology and increasingly are exploited as antibiotic targets. SurA is the most important chaperone OMP biogenesis network thought to initiate their folding through an interaction with BAM complex. We observe unprecedented expansion of unfolded outer when bound SurA. This suggests a potential mechanism by which can deliver uOMPs In addition, this study highlights use integrative/hybrid structural biology approach...
Through the insertion of nonpolar side chains into bilayer, hydrophobic effect has long been accepted as a driving force for membrane protein folding. However, how changing chemical composition bilayer affects magnitude side-chain transfer free energies (ΔGsc°) historically not well understood. A particularly challenging region experimental interrogation is interfacial that characterized by steep polarity gradient. In this study, we have determined ΔGsc° function position using combination...
G protein–coupled receptors (GPCRs) control intracellular signaling cascades via agonist-dependent coupling to transducers including heterotrimeric proteins, GPCR kinases (GRKs), and arrestins. In addition their critical interactions with the transmembrane core of active GPCRs, all three classes have also been reported interact receptor C-terminal domains (CTDs). An underexplored aspect CTDs is possible role as lipid sensors given proximity membrane. CTD–membrane potential accessibility key...
SurA is thought to be the most important periplasmic chaperone for outer membrane protein (OMP) biogenesis. Its structure composed of a core region and two peptidylprolyl isomerase domains, termed P1 P2, connected by flexible linkers. As such these three independent folding units are able adopt number distinct spatial positions with respect each other. The conformational dynamics domains functionally yet largely unresolved. Here we address this question ensemble using sedimentation...
Abstract A recently developed flexible three-site model for methanol was employed to perform a Molecular Dynamics simulation of 0.6 molal NaCl solution. The ion-methanol and ion-ion potential functions were derived from ab initio calculations. structural properties the solution are discussed on basis radial angular distribution functions, orientation molecules, their geometrical arrangement in solvation shells ions. dynamical - like self-diffusion coefficients, hindered translations,...
Abstract Outer membrane protein (OMP) biogenesis in gram‐negative bacteria is managed by a network of periplasmic chaperones that includes SurA, Skp, and FkpA. These bind unfolded OMPs (uOMPs) dynamic conformational ensembles to suppress aggregation, facilitate diffusion across the periplasm, enhance folding. FkpA primarily responds heat‐shock stress, but its mechanism comparatively understudied. To determine chaperone function context OMP folding, we monitored folding three found FkpA,...
Abstract The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane (TMDs) drive intracellular signaling. Pharmacologically, mGluRs can be targeted either at the LBDs by synthetic orthosteric compounds or TMDs allosteric modulators. Despite potential of TMD-targeting therapeutics, an understanding functional structural basis their effects on is...
Abstract G protein-coupled receptors (GPCRs) control intracellular signaling cascades via agonist-dependent coupling to transducers including heterotrimeric proteins, GPCR kinases (GRKs), and arrestins. In addition their critical interactions with the transmembrane core of active GPCRs, all three classes have also been reported interact receptor C-terminal domains (CTDs). An underexplored aspect CTDs is possible role as lipid sensors given proximity membrane. CTD-membrane potential...
Abstract The periplasmic chaperone network ensures the biogenesis of bacterial outer membrane proteins (OMPs) and has recently been identified as a promising target for antibiotics. SurA is most important member this both due to its genetic interaction with β-barrel assembly machinery complex well ability prevent unfolded OMP (uOMP) aggregation. Using only binding energy, mechanism by which carries out these two functions not understood. Here we use combination photo-crosslinking, mass...
ABSTRACT Through the insertion of nonpolar side chains into bilayer, hydrophobic effect has long been accepted as a driving force for membrane protein folding. However, how changing chemical composition bilayer affects magnitude chain transfer free energies historically not well understood. A particularly challenging region experimental interrogation is interfacial that characterized by steep polarity gradient. In this study we have determined function position using combination experiment...