Miles Sasha Dickinson
A5074079408- SARS-CoV-2 and COVID-19 Research
- RNA and protein synthesis mechanisms
- Microbial Natural Products and Biosynthesis
- Bacteriophages and microbial interactions
- Monoclonal and Polyclonal Antibodies Research
- Ion channel regulation and function
- Calcium signaling and nucleotide metabolism
- Biochemical and Molecular Research
- Plant and Biological Electrophysiology Studies
- Photosynthetic Processes and Mechanisms
- Plant Stress Responses and Tolerance
- Cytomegalovirus and herpesvirus research
- Photoreceptor and optogenetics research
- Enzyme Structure and Function
- Genomics and Chromatin Dynamics
- Protein Degradation and Inhibitors
- Microtubule and mitosis dynamics
- Genomics and Phylogenetic Studies
- Chromosomal and Genetic Variations
- interferon and immune responses
- Advanced Electron Microscopy Techniques and Applications
- Adenosine and Purinergic Signaling
- Ubiquitin and proteasome pathways
- Advanced Memory and Neural Computing
- vaccines and immunoinformatics approaches
University of Washington
2016-2024
University of California, San Francisco
2018-2023
Seattle University
2022-2023
The University of Texas at Austin
2022
Molecular Biology Consortium
2020-2021
Quantitative BioSciences
2020
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 closely related more lethal but less transmissible coronaviruses SARS-CoV-1 Middle East (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the cell receptor angiotensin-converting enzyme (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt ACE2. Cryo-electron microscopy (cryo-EM) revealed one nanobody, Nb6, binds in fully inactive conformation with binding domains locked into their inaccessible down state, incapable...
Abstract A wooden house frame consists of many different lumber pieces, but because the regularity these building blocks, structure can be designed using straightforward geometrical principles. The design multicomponent protein assemblies, in comparison, has been much more complex, largely owing to irregular shapes structures 1 . Here we describe extendable linear, curved and angled as well inter-block interactions, that conform specified geometric standards; assemblies blocks inherit their...
Abstract The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis those remain unknown. Here, we report an atomic model for full-length obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. resulting reveals highly-conserved zinc ion-binding site, suggesting role RNA binding. Mapping emerging mutations variants on shows potential host-Nsp2 interaction regions....
Inosine monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in guanosine triphosphate (GTP) synthesis and assembles into filaments cells, which desensitizes to feedback inhibition boosts nucleotide production. The vertebrate retina expresses two splice variants IMPDH1(546) IMPDH1(595). In bovine retinas, residue S477 preferentially phosphorylated dark, but effects on IMPDH1 activity regulation are unclear. Here, we generated phosphomimetic mutants investigate structural...
Significance Despite decades of biophysical and structural research, little is understood about how voltage-gated ion channels (VGICs) activate during membrane depolarization, less known VGICs can be modulated by lipids other ligands. We identify multiple functional states the voltage- Ca 2+ -gated channel TPC1 from Arabidopsis thaliana (AtTPC1), which confers electrical excitability to plant vacuole. Here, we show a voltage-sensing domain (VSD) functions activation mechanism inhibition...
ABSTRACT Although the primary protein sequence of ubiquitin (Ub) is extremely stable over evolutionary time, it highly tolerant to mutation during selection experiments performed in laboratory. We have proposed that this discrepancy results from difference between fitness under laboratory culture conditions and selective pressures changing environments timescales. Building on our previous work (Mavor et al., 2016), we used deep mutational scanning determine how twelve new chemicals...
Voltage-gated ion channels endow membranes with excitability and the means to propagate action potentials that form basis of all neuronal signaling. We determined structure a voltage-gated sodium channel, two-pore channel 3 (TPC3), which generates ultralong potentials. TPC3 is distinguished by activation only at extreme membrane depolarization (V 50 ∼ +75 mV), in contrast other TPCs Na V activate between −20 0 mV. present electrophysiological evidence voltage depends on sensing domain 2...
The SARS-CoV-2 protein Nsp2 has been implicated in a wide range of viral processes, but its exact functions, and the structural basis those remain unknown. Here, we report an atomic model for full-length obtained by combining cryo-electron microscopy with deep learning-based structure prediction from AlphaFold2. resulting reveals highly-conserved zinc ion-binding site, suggesting role RNA binding. Mapping emerging mutations variants on shows potential host-Nsp2 interaction regions. Using...
Plants obtain nutrients from the soil via transmembrane transporters and channels in their root hairs, which ions radially transport toward xylem for distribution across plant body. We determined structures of hyperpolarization-activated channel AKT1 Arabidopsis thaliana, mediates K+ uptake into roots. These AtAKT1 embedded lipid nanodiscs show that undergoes a reduction C4 to C2 symmetry, possibly regulate its electrical activation.
Abstract A wooden house frame consists of many different lumber pieces, but because the regularity these building blocks, structure can be designed using straightforward geometrical principles. The design multicomponent protein assemblies in comparison has been much more complex, largely due to irregular shapes structures 1 . Here we describe extendable linear, curved, and angled as well inter-block interactions that conform specified geometric standards; blocks inherit their extendability...
Mycobacterium tuberculosis is currently the leading cause of death by any bacterial infection1. The mycolic acid layer cell wall essential for viability and virulence, enzymes responsible its synthesis are therefore front line targets antimycobacterial drug development2,3. Polyketide synthase 13 (Pks13) a module comprised closely symmetric parallel dimer chains, each encoding several enzymatic transport functions, that carries out condensation two different very long chain fatty acids to...
To fire action-potential-like electrical signals, the vacuole membrane requires two-pore channel TPC1, formerly called SV channel. The TPC1/SV functions as a depolarization-stimulated, non-selective cation that is inhibited by luminal Ca 2+ . In our search for species-dependent functional TPC1 variants with different sensitivity, we found in total three acidic residues present sensor sites 2 and 3 of -sensitive AtTPC1 from Arabidopsis thaliana were neutral its Vicia faba ortholog also those...
Porcine deltacoronavirus (PDCoV) spillovers were recently detected in children with acute undifferentiated febrile illness, underscoring recurrent zoonoses of divergent coronaviruses. To date, no vaccines or specific therapeutics are approved for use humans against PDCoV. prepare possible future PDCoV epidemics, we isolated human spike (S)-directed monoclonal antibodies from transgenic mice and found that two them, designated PD33 PD41, broadly neutralized a panel variants. Cryo-electron...
Porcine delta-coronavirus (PDCoV) spillovers were recently detected in febrile children, underscoring the recurrent zoonoses of divergent CoVs. To date, no vaccines or specific therapeutics are approved for use humans against PDCoV. prepare possible future PDCoV epidemics, we isolated spike (S)-directed monoclonal antibodies (mAbs) from humanized mice and found that two, designated PD33 PD41, broadly neutralized a panel variants. Cryoelectron microscopy (cryo-EM) structures PD41 complex with...
Abstract A critical step in infections is the attachment of many microorganisms to host cells using lectins that bind surface glycans, making promising antimicrobial targets. Upon binding mannosylated FimH, most studied lectin adhesin type 1 fimbriae E. coli , undergoes an allosteric transition from inactive active conformation can act as a catch-bond. Monoclonal antibodies alter FimH glycan various ways are available, but mechanisms these remain unclear. Here, we use cryoEM, mass...
Summary Forcing budding yeast to chromatinize their DNA with human histones manifests an abrupt fitness cost. We previously proposed chromosomal aneuploidy and missense mutations as two potential modes of adaptation histone humanization. Here we show that in histone-humanized yeasts is specific a subset chromosomes, defined by centromeric evolutionary origins, however, they are not adaptive. Instead set outer kineto-chore proteins drive histones. Further, characterize the molecular mechanism...
ABSTRACT Inosine monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in de novo guanosine triphosphate (GTP) synthesis and controlled by feedback inhibition allosteric regulation. IMPDH assembles into micron-scale filaments cells, which desensitizes to GTP boosts nucleotide production. The vertebrate retina expresses two tissue-specific splice variants IMPDH1(546) IMPDH1(595). adopt high low activity conformations, while IMPDH1(595) maintain activity. In bovine retinas, residue...