A5070240148- Receptor Mechanisms and Signaling
- Protein Structure and Dynamics
- Neuropeptides and Animal Physiology
- Pharmacological Receptor Mechanisms and Effects
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Mass Spectrometry Techniques and Applications
- Lipid Membrane Structure and Behavior
- Diabetes Treatment and Management
- Photoreceptor and optogenetics research
- Cannabis and Cannabinoid Research
- Pancreatic function and diabetes
- Neuroscience and Neuropharmacology Research
- Advanced NMR Techniques and Applications
- Fullerene Chemistry and Applications
- Advanced Proteomics Techniques and Applications
- Enzyme Structure and Function
- Inorganic Chemistry and Materials
- Marine Biology and Ecology Research
- Chemical Reactions and Isotopes
- Advanced biosensing and bioanalysis techniques
- Molecular spectroscopy and chirality
- Advanced Biosensing Techniques and Applications
- Nanocluster Synthesis and Applications
- Nanotechnology research and applications
Stanford University
2020-2025
Johns Hopkins Medicine
2025
Johns Hopkins University
2025
University of California, Santa Cruz
2023-2024
Columbia University
2016-2021
University of Pennsylvania
2014-2020
Johnson Foundation
2014-2020
Texas A&M University
2018
Abstract The µ-opioid receptor (µOR) is an important target for pain management 1 and molecular understanding of drug action on µOR will facilitate the development better therapeutics. Here we show, using double electron–electron resonance single-molecule fluorescence energy transfer, how ligand-specific conformational changes translate into a broad range intrinsic efficacies at transducer level. We identify several conformations cytoplasmic face that interconvert different timescales,...
Family B heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) play important roles in carbohydrate metabolism. Recent structures of family GPCR-Gs complexes reveal a disruption the α-helix transmembrane segment 6 (TM6) not observed A GPCRs. To investigate functional impact this structural difference, we compared structure and function glucagon receptor (GCGR; B) with β2 adrenergic (β2AR; A). We determined GCGR-Gs complex by means cryo-electron microscopy at...
SignificanceDeep profiling of the plasma proteome at scale has been a challenge for traditional approaches. We achieve superior performance across dimensions precision, depth, and throughput using panel surface-functionalized superparamagnetic nanoparticles in comparison to conventional workflows deep proteomics interrogation. Our automated workflow leverages competitive nanoparticle-protein binding equilibria that quantitatively compress large dynamic range proteomes an accessible scale....
Introducing engineered nanoparticles (NPs) into a biofluid such as blood plasma leads to the formation of selective and reproducible protein corona at particle-protein interface, driven by relationship between protein-NP affinity abundance. This enables scalable systems that leverage protein-nano interactions overcome current limitations deep proteomics in large cohorts. Here importance NP-surface ratio (P/NP) is demonstrated dynamics are modeled, which determine competition proteins for...
Molecular dynamics simulations are used to analyze the relationship between NMR-derived squared generalized order parameters of amide NH groups and backbone entropy. Amide (O2NH) largely determined by secondary structure average values appear unrelated overall flexibility protein. However, analysis more flexible subset (O2NH < 0.8) shows that these report both on local protein a different component conformational entropy than reported side chain methyl axis parameters, O2axis. A calibration...
The interaction between cytochrome c and the anionic lipid cardiolipin has been proposed as a primary event in apoptotic signaling cascade. Numerous studies that have examined of with embedded variety model phospholipid membranes suggested partial unfolding protein is precursor to response. However, these lacked site resolution used systems negligible or positive membrane curvature, which distinct from large negative curvature invaginations inner mitochondrial where resides. We reverse...
An optimized reverse micelle surfactant system has been developed for solution nuclear magnetic resonance studies of encapsulated proteins and nucleic acids dissolved in low viscosity fluids. Comprising the nonionic 1-decanoyl-rac-glycerol zwitterionic lauryldimethylamine-N-oxide (10MAG/LDAO), this mixture is shown to efficiently encapsulate a diverse set acids. Chemical shift analyses these systems show that high structural fidelity achieved upon encapsulation. The 10MAG/LDAO reduces...
Virtual library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking agonists for cannabinoid-1 receptor (CB1R), we dock 74 million tangible molecules and prioritize 46 high ranking ones de novo synthesis testing. Nine are active by radioligand competition, a 20% hit-rate. Structure-based optimization one most potent these (Ki = 0.7 µM) leads to '1350, 0.95 nM ligand full CB1R agonist Gi/o signaling. A cryo-EM structure '1350 in complex with...
Variation in environmental conditions across a species' range can alter their responses to change through local adaptation and acclimation. Evolutionary responses, however, may be challenged ecosystems with tightly coupled conditions, where changes the covariance of factors make it more difficult for species adapt global change. Here, we conduct 3-month-long mesocosm experiment find evidence adaptation/acclimation populations red sea urchins, Mesocentrotus franciscanus, multiple drivers....
Molecular dynamics (MD) simulations have become a central tool for investigating various biophysical questions with atomistic detail. While many different proxies are used to qualify MD force fields, most based on largely structural parameters such as the root mean square deviation from experimental coordinates or nuclear magnetic resonance (NMR) chemical shifts and residual dipolar couplings. NMR derived Lipari-Szabo squared generalized order parameter (O(2) ) values of amide NH bond...
Abstract The internal motions of integral membrane proteins have largely eluded comprehensive experimental characterization. Here the fast side‐chain dynamics α‐helical sensory rhodopsin II and β‐barrel outer protein W been investigated in lipid bilayers detergent micelles by solution NMR relaxation techniques. Despite their differing topologies, both a similar distribution methyl‐bearing motion that is independent mimetic. side chains are, on average, more dynamic ps–ns timescale than any...
Structural phase transitions run in families of crystalline solids. Perovskites, for example, feature a remarkable number structural transformations that produce wealth exotic behaviors, including ferroelectricity, magnetoresistance, metal-insulator and superconductivity. In superatomic crystals other such materials assembled from programmable building blocks, offer pathways to new properties are both tunable switchable. Here we describe [Co6Te8(PEt3)6][C70]2, novel crystal with two separate...
Abstract The μ-opioid receptor (μOR) is an important target for pain management and the molecular understanding of drug action will facilitate development better therapeutics. Here we show, using double electron-electron resonance (DEER) single-molecule fluorescence energy transfer (smFRET), how ligand-specific conformational changes μOR translate into a broad range intrinsic efficacies at transducer level. We identify several cytoplasmic conformations interconverting on different...
Abstract Variability in primary producers' responses to environmental change may buffer higher trophic levels against shifts basal resource composition. Then again, instances where there is a lack of functional redundancy because consumers rely on few species meet their energetic requirements at specific times the year, altered community production dynamics significantly impact food web resilience. In high‐latitude kelp forests, complementary annual phenology seaweed supports coastal marine...