A5071273237- Enzyme Structure and Function
- Protein Structure and Dynamics
- Liver physiology and pathology
- Lung Cancer Treatments and Mutations
- PI3K/AKT/mTOR signaling in cancer
- Advanced X-ray Imaging Techniques
- Chemical Reactions and Isotopes
- Cancer Mechanisms and Therapy
- Signaling Pathways in Disease
- Particle Accelerators and Free-Electron Lasers
- Glutathione Transferases and Polymorphisms
- Macrophage Migration Inhibitory Factor
- Bioactive Compounds and Antitumor Agents
- Cancer therapeutics and mechanisms
- Advanced Electron Microscopy Techniques and Applications
- Biochemical and Molecular Research
- Ubiquitin and proteasome pathways
- Particle accelerators and beam dynamics
- Hepatocellular Carcinoma Treatment and Prognosis
- Protein Degradation and Inhibitors
- Research on Leishmaniasis Studies
- Advancements in Photolithography Techniques
- Machine Learning in Materials Science
- Geophysical and Geoelectrical Methods
- Porphyrin Metabolism and Disorders
University of California, Merced
2021-2024
University of California, San Francisco
2017-2022
University of Hyogo
2019
Bioengineering Center
2019
SPring-8
2019
Kyoto University
2019
Stanford University
1986
SLAC National Accelerator Laboratory
1986
Stanford Synchrotron Radiation Lightsource
1986
Although patients with advanced-stage non-small cell lung cancers (NSCLC) harboring MET exon 14 skipping mutations (METex14) often benefit from tyrosine kinase inhibitor (TKI) treatment, clinical is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained 289 METex14-mutated NSCLC.Prominent co-occurring RAS-MAPK pathway gene alterations (e.g.,...
Abstract Understanding and controlling protein motion at atomic resolution is a hallmark challenge for structural biologists engineers because conformational dynamics are essential complex functions such as enzyme catalysis allosteric regulation. Time-resolved crystallography offers window into motions, yet without universal perturbation to initiate changes the method has been limited in scope. Here we couple solvent-based temperature jump with time-resolved visualize motions lysozyme,...
Enzymes populate ensembles of structures necessary for catalysis that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography at an x-ray free electron laser observe in a designed mutant isocyanide hydratase (ICH) enzyme enhances sampling important minor conformations. The active site exists mixture conformations, and formation the thioimidate intermediate selects catalytically competent substates. influence cysteine ionization on ICH ensemble...
Innovative new crystallographic methods are facilitating structural studies from ever smaller crystals of biological macromolecules. In particular, serial X-ray crystallography and microcrystal electron diffraction (MicroED) have emerged as useful for obtaining information on the nanometre to micrometre scale. Despite utility these methods, their implementation can often be difficult, they present many challenges that not encountered in traditional macromolecular experiments. Here, XFEL...
It is investigated whether molecular-dynamics (MD) simulations can be used to enhance macromolecular crystallography (MX) studies. Historically, protein crystal structures have been described using a single set of atomic coordinates. Because conformational variation important for function, researchers now often build models that contain multiple structures. Methods building such fail, however, in regions where the crystallographic density difficult interpret, example at protein–solvent...
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...
Summary Understanding and controlling protein motion at atomic resolution is a hallmark challenge for structural biologists engineers because conformational dynamics are essential complex functions such as enzyme catalysis allosteric regulation. Time-resolved crystallography offers window into motions, yet without universal perturbation to initiate changes the method has been limited in scope. Here we couple solvent-based temperature jump with time-resolved visualize motions lysozyme,...
Systematic analysis of molecular recognition is critical for understanding the biological function macromolecules. For immunomodulatory protein D-dopachrome tautomerase (D-DT), mechanism protein-ligand interactions poorly understood. Here, 17 carefully designed variants and wild type (WT) D-DT were interrogated with an array complementary techniques to elucidate structural basis ligand recognition. Utilization a substrate two selective inhibitors distinct binding profiles offered previously...
Abstract Correlated motions of proteins and their bound solvent molecules are critical to function, but these features difficult resolve using traditional structure determination techniques. Time-resolved methods hold promise for addressing this challenge have relied on the exploitation exotic protein photoactivity, therefore not generalizable. Temperature-jumps (T-jumps), through thermal excitation solvent, been implemented study dynamics spectroscopic techniques, implementation in X-ray...
Abstract To assess the potential benefits of molecular-dynamics (MD) simulations for macromolecular crystallography (MX), we performed room-temperature X-ray diffraction studies catalytic subunit mouse protein kinase A (PKA-C). We then crystalline MD PKA-C, computed simulated electron densities from water, protein, and ion components simulations, carefully compared them to initial crystal structure. The results led development an MD-MX analysis procedure several associated methods: 1)...
Enzymes populate ensembles of structures with intrinsically different catalytic proficiencies that are difficult to experimentally characterize. We use time-resolved mix-and-inject serial crystallography (MISC) at an X-ray free electron laser (XFEL) observe catalysis in a designed mutant (G150T) isocyanide hydratase (ICH) enzyme enhances sampling important minor conformations. The active site exists mixture conformations and formation the thioimidate intermediate selects for catalytically...
Abstract PURPOSE While patients with advanced-stage non-small cell lung cancers (NSCLCs) harboring MET exon 14 skipping mutations ( METex 14) often benefit from tyrosine kinase inhibitor (TKI) treatment, clinical is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood. METHODS Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained 289 14-mutated NSCLC. RESULTS Prominent co-occurring RAS-MAPK...
Abstract Innovative new crystallographic methods are facilitating structural studies from ever smaller crystals of biological macromolecules. In particular, serial X-ray crystallography and microcrystal electron diffraction (MicroED) have emerged as useful for obtaining information on the nanometer to micron scale. Despite utility these methods, their implementation can often be difficult, they present many challenges not encountered in traditional macromolecular experiments. Here, we...
<p>The MET F1200 residue is conserved across multiple tyrosine kinases</p>
<p>Summary of mutation clonality across patient cohorts</p>
<p>KRAS amplification and/or KRAS G12D mutation in METex14-mutated NSCLC with resistance to crizotinib</p>
<p>Demographics of the METex14-mutated and EGFR-mutated cohorts.</p>
<p>Genes included in NGS Panels</p>
<p>Flowchart describing sample filtering for predicted functional impact.</p>
<p>MET tyrosine kinase domain modeling location of the F1200 residue</p>
<p>Relative cell viability of Ba/F3 METex14-mutant expressing cells treated with trametinib monotherapy</p>
<div>AbstractPurpose:<p>Although patients with advanced-stage non–small cell lung cancers (NSCLC) harboring <i>MET</i> exon 14 skipping mutations (<i>MET</i>ex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.</p>Experimental Design:<p>Targeted sequencing analysis was performed on cell-free...