A5041661036- Receptor Mechanisms and Signaling
- Biochemical Analysis and Sensing Techniques
- Psychedelics and Drug Studies
- RNA and protein synthesis mechanisms
- Chemical synthesis and alkaloids
- Hemoglobin structure and function
- Neuropeptides and Animal Physiology
- High Altitude and Hypoxia
- Magnetic properties of thin films
- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Heme Oxygenase-1 and Carbon Monoxide
- RNA regulation and disease
- Advanced Electron Microscopy Techniques and Applications
- Animal Virus Infections Studies
- Neurotransmitter Receptor Influence on Behavior
- Pharmacological Receptor Mechanisms and Effects
- Mass Spectrometry Techniques and Applications
- Influenza Virus Research Studies
- Chemical Synthesis and Analysis
- Viral Infections and Vectors
- RNA modifications and cancer
- Virology and Viral Diseases
- Neuroscience and Neuropharmacology Research
- Enzyme Structure and Function
University of North Carolina at Chapel Hill
2021-2025
Georgia State University
2015-2023
University of North Carolina Health Care
2023
Leipzig University
2018
AlphaFold2 (AF2) models have had wide impact but mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 of the σ
RNA editing is a process by which post-transcriptional changes of mRNA nucleotides alter protein function through modification the amino acid content. The 5HT2C serotonin receptor, undergoes 32 distinct RNA-editing events leading to 24 isoforms, notable example this process. These isoforms display differences in constitutive activity, agonist/inverse agonist potencies, and efficacies. To elucidate molecular mechanisms responsible for these effects editing, we present four active-state...
Abstract AlphaFold2 (AF2) and RosettaFold have greatly expanded the number of structures available for structure-based ligand discovery, even though retrospective studies cast doubt on their direct usefulness that goal. Here, we tested unrefined AF2 models prospectively , comparing experimental hit-rates affinities from large library docking against vs same screens targeting receptors. In σ 2 5-HT2A receptors, struggled to recapitulate ligands had previously found receptors’ structures,...
There is currently a resurgence in exploring the utility of classical psychedelics to treat depression, addiction, anxiety disorders, cluster headaches, and many other neuropsychiatric disorders. A biological target these compounds, hypothesized for their therapeutic actions, 5-HT2A serotonin receptor. Here, we present 7 cryo-EM structures covering all major compound classes psychedelic non-psychedelic agonists, including β-arrestin-biased RS130-180. Identifying molecular interactions...
The master transcriptional regulator PU.1/Spi-1 engages DNA sites with affinities spanning multiple orders of magnitude. To elucidate this remarkable plasticity, we have characterized 22 high-resolution co-crystallographic PU.1/DNA complexes across the addressable affinity range in myeloid gene transactivation. Over a purine-rich core (such as 5'-GGAA-3') flanked by variable sequences, is negotiated direct readout on 5' flank via critical glutamine (Q226) sidechain and indirect 3'...
Negative-strand RNA viruses (NSVs) include the most pathogenic known. New methods to monitor their evolutionary trends are urgently needed for development of antivirals and vaccines. The protein translation machinery host cell is currently recognized as a main genomic regulator virus evolution, which works especially well positive-strand viruses. However, this approach fails NSVs because it does not consider unique mechanism viral synthesis. For NSVs, RNA-dependent polymerase (vRdRp) must...
ABSTRACT Polyamides have been shown to bind double-stranded DNA by complementing the curvature of minor groove and forming various hydrogen bonds with DNA. Several polyamide molecules found potent antiviral activities against papillomavirus, a virus. By analogy, we reason that polyamides may also interact structured RNA bound in nucleocapsid negative-strand Vesicular stomatitis virus (VSV) was selected as prototype test this possibility since its genomic encapsidated forms structure...
During viral RNA synthesis by the RNA-dependent polymerase (vRdRp) of vesicular stomatitis virus, sequestered genome must be released from nucleocapsid in order to serve as template. Unveiling interactions vRdRp proteins, large subunit (L) and phosphoprotein (P), with protein (N) not disrupt assembly. We noticed that a flexible structural motif composed an α-helix loop N may act access gate RNA. This suggests local conformational changes this induced unveil RNA, without disrupting Mutations...
This brief review highlights some of the structure-activity relationships classic serotonergic psychedelics. In particular, we discuss structural features three chemotypes: phenethylamines, ergolines, and certain tryptamines, which possess psychedelic activity in humans. Where it is known, point out underlying molecular mechanisms utilized by each chemotypes molecules. With a focus on serotonin 5-HT2A receptor subtype, G-protein coupled known to be primary target psychedelics, reference...