A5066732409- Mass Spectrometry Techniques and Applications
- Biochemical and Molecular Research
- Metabolomics and Mass Spectrometry Studies
- Estrogen and related hormone effects
- Receptor Mechanisms and Signaling
- Adipose Tissue and Metabolism
- Enzyme Structure and Function
- HIV/AIDS drug development and treatment
- Cytokine Signaling Pathways and Interactions
- Immune cells in cancer
- Peroxisome Proliferator-Activated Receptors
- Immune Response and Inflammation
- Protein Kinase Regulation and GTPase Signaling
- Electrostatic Discharge in Electronics
- Analytical Chemistry and Chromatography
- Viral Infections and Immunology Research
- RNA and protein synthesis mechanisms
- Nuclear Receptors and Signaling
- Retinoids in leukemia and cellular processes
- Electron and X-Ray Spectroscopy Techniques
- Cancer, Hypoxia, and Metabolism
- CRISPR and Genetic Engineering
- Advanced Electron Microscopy Techniques and Applications
- HIV Research and Treatment
- PARP inhibition in cancer therapy
Salk Institute for Biological Studies
2022-2025
Scripps Research Institute
2017-2022
Scripps (United States)
2022
The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
2022
ORCID
2019
University of Iowa
2014-2018
Adenosine monophosphate (AMP)-activated protein kinase (AMPK) regulates metabolism in response to the cellular energy states. Under stress, AMP stabilizes active AMPK conformation, which activation loop (AL) is protected from phosphatases, thus keeping AL its active, phosphorylated state. At low AMP:ATP (adenosine triphosphate) ratios, ATP inhibits by increasing dynamics and accessibility. We developed conformation-specific antibodies trap ATP-bound a fully inactive, dynamic state determined...
Not your typical GPCR Among the large family of G protein–coupled receptors (GPCRs) are many orphans, so called because their signaling reactions remain poorly understood. these is GPR158 which highly expressed in nervous system and implicated processes from cognition to memory mood. Patil et al . determined a high-resolution structure alone bound regulator protein (RGS) complex. has an unusual dimerization mode with extensive interaction interface that locks it conformation likely prevents...
HIV-1 infection depends on the integration of viral DNA into host chromatin. Integration is mediated by enzyme integrase and blocked strand transfer inhibitors (INSTIs), first-line antiretroviral therapeutics widely used in clinic. Resistance to even best INSTIs a problem, mechanisms resistance are poorly understood. Here, we analyze combinations mutations E138K, G140A/S, Q148H/K/R, which confer INSTIs. The investigational drug 4d more effectively inhibited mutants compared with approved...
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 has triggered an ongoing global pandemic whereby infection may result a lethal pneumonia-like disease designated as (COVID-19). To date, millions confirmed cases and hundreds thousands deaths have been reported worldwide, there are currently no medical countermeasures available to prevent or treat the disease. purported development vaccine could require at least 1–4 years, while typical timeline from...
Abstract Circularized nandiscs (cNDs) exhibit superb monodispersity and have the potential to transform functional structural studies of membrane proteins. In particular, cNDs can stabilize large patches lipid bilayers for reconstitution complex biochemical reactions, enabling capture crucial intermediates involved in synaptic transmission viral entry. However, previous methods building require multiple steps suffer from low yields. We herein introduce a simple, one-step approach ease...
The retinoic acid-related orphan receptor gamma (RORγt) acts as the major transcriptional activator in Th17 cell development and function to mediate adaptive immune defenses against pathogenic infection. RORγt engages accessible DNA response elements genome interplays with coactivator proteins accessory transcription factors drive gene expression. However, how chromatin environment mediates structure, dynamics, remains unclear. Here, we profile nucleosome promotes or restricts access main...
Protein poly-ADP-ribosylation (PARylation) is a heterogeneous and dynamic post-translational modification regulated by various writers, readers, erasers. It participates in variety of biological events involved many human diseases. Currently, tools technologies have yet to be developed for unambiguously defining readers erasers individual PARylated proteins or cognate known Here, we report the generation bifunctional nicotinamide adenine dinucleotide (NAD+) characterized diazirine-modified...
An analogue of nicotinamide adenine dinucleotide (NAD + ) featuring an azido group at 3′-OH adenosine moiety is found to possess high specificity for human PARP1-catalyzed protein poly-ADP-ribosylation.
Thymidylate synthase (TSase) catalyzes the intracellular de novo formation of thymidylate (a DNA building block) in most living organisms, making it a common target for chemotherapeutic and antibiotic drugs. Two mechanisms have been proposed rate-limiting hydride transfer step TSase catalysis: stepwise mechanism which precedes cleavage covalent bond between enzymatic cysteine product where both happen concertedly. Striking similarities enzyme-bound enolate intermediates formed initial final...
N-Acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration N-acyl to mice improves glucose homeostasis increases energy expenditure, indicating this pathway might be useful for treating obesity associated disorders. report the full account synthesis mitochondrial uncoupling bioactivity lipidated their unnatural analogues. Unsaturated fatty acid chains medium length neutral head groups are required optimal...
Members of the nuclear receptor (NR) superfamily regulate both physiological and pathophysiological processes ranging from development metabolism to inflammation cancer. Synthetic small molecules targeting NRs are often deployed as therapeutics correct aberrant NR signaling or chemical probes explore role in physiology. Nearly half do not have specific cognate ligands (termed orphan NRs) it’s unclear if they possess ligand dependent activities. Here we demonstrate that ligand-dependent...
Heme is the endogenous ligand for constitutively repressive REV-ERB nuclear receptors, REV-ERBα (NR1D1) and REV-ERBβ (NR1D2), but how heme regulates activity remains unclear. Cellular studies indicate that required REV-ERBs to bind corepressor NCoR repress transcription. However, fluorescence-based biochemical assays suggest displaces NCoR; here, we show this due a heme-dependent artifact. Using ITC NMR spectroscopy, binding remodels thermodynamic interaction profile of receptor domain (RID)...
Thymidylate Synthase (TSase) is a highly conserved enzyme that catalyzes the production of DNA building block thymidylate. Structurally, functionally and mechanistically, bacterial mammalian TSases share remarkable similarities. Because this closeness, enzymes have long been used as model systems for human TSase. Furthermore, while TSase inhibitors served chemotherapeutic drugs, no inhibitor serves an antibiotic. Despite their high resemblance, are distinct in few known aspects, such having...
Hydrogen/Deuterium Exchange (HDX) coupled with Mass Spectrometry (HDX-MS) is a sensitive and robust method to probe protein conformational changes protein-ligand interactions. HDX-MS relies on successful proteolytic digestion of target proteins under acidic conditions localize perturbations in exchange behavior structure. The ability the protease produce small peptides overlapping fragments provide sufficient coverage sequence essential for localizing regions interest. While acid pepsin has...
Obesity and rheumatic disease are mechanistically linked via chronic inflammation. The orphan receptor TREM-1 (triggering expressed on myeloid cells-1) is a potent amplifier of proinflammatory noninfectious immune responses. Here, we show that the pan modulator SR1903 effectively blocks activation. emerged from chemical series RORγ inverse agonists, although unlike close structural analogues, it has modest agonist activity LXR weak repressive (inverse agonism) PPARγ, three receptors play...
Thymidylate synthase (TSase) catalyzes the de novo biosynthesis of thymidylate, a precursor for DNA, and is thus an important target chemotherapeutics antibiotics. Two sequential C–H bond cleavages catalyzed by TSase are particular interest: reversible proton abstraction from 2′-deoxyuridylate substrate, followed irreversible hydride transfer forming thymidylate product. QM/MM calculations former predicted mechanism in which leads to formation novel nucleotide-folate intermediate that not...
Single-particle analysis (SPA) by cryo-electron microscopy (cryo-EM) is now a mainstream technique for high-resolution structural biology. Structure determination SPA relies upon obtaining multiple distinct views of macromolecular object vitrified within thin layer ice. Ideally, collection uniformly distributed random projection orientations would amount to all possible the object, giving rise reconstructions characterized isotropic directional resolution. However, in reality, many samples...