A5086921160- PI3K/AKT/mTOR signaling in cancer
- Protein Kinase Regulation and GTPase Signaling
- Cellular transport and secretion
- Chronic Lymphocytic Leukemia Research
- Receptor Mechanisms and Signaling
- Monoclonal and Polyclonal Antibodies Research
- Ubiquitin and proteasome pathways
- Mass Spectrometry Techniques and Applications
- Biochemical and Molecular Research
- Methane Hydrates and Related Phenomena
- RNA and protein synthesis mechanisms
- Calcium signaling and nucleotide metabolism
- Lipid metabolism and biosynthesis
- Lipid Membrane Structure and Behavior
- Tuberculosis Research and Epidemiology
- Cancer-related Molecular Pathways
- Seismic Waves and Analysis
- Endoplasmic Reticulum Stress and Disease
- Erythrocyte Function and Pathophysiology
- Microtubule and mitosis dynamics
- Earthquake Detection and Analysis
- Metabolomics and Mass Spectrometry Studies
- Venomous Animal Envenomation and Studies
- Escherichia coli research studies
- Enzyme Structure and Function
University of British Columbia
2020-2025
University of Victoria
2016-2025
Oregon Health & Science University
2023
Boston Children's Hospital
2023
Harvard University
2023
University of Oregon
2023
ORCID
2023
MRC Laboratory of Molecular Biology
2011-2016
Medical Research Council
2011-2016
European Molecular Biology Laboratory
2016
Deep learning takes on protein folding In 1972, Anfinsen won a Nobel prize for demonstrating connection between protein’s amino acid sequence and its three-dimensional structure. Since 1994, scientists have competed in the biannual Critical Assessment of Structure Prediction (CASP) protein-folding challenge. methods took center stage at CASP14, with DeepMind’s Alphafold2 achieving remarkable accuracy. Baek et al . explored network architectures based DeepMind framework. They used three-track...
The p110α catalytic subunit ( PIK3CA ) is one of the most frequently mutated genes in cancer. We have examined activation wild-type p110α/p85α and a spectrum oncogenic mutants using hydrogen/deuterium exchange mass spectrometry (HDX-MS). find that for enzyme, natural transition from an inactive cytosolic conformation to activated form on membranes entails four distinct events. Analysis mutations shows all up-regulate enzyme by enhancing or more these dynamic provide first insight into...
Opening up Vps34 protein complexes During intracellular membrane trafficking, large regulate and adapt the activity of signal transducer enzymes such as class III phosphatidylinositol 3-kinase Vps34. These enzyme are present in all eukaryotic cells, having widespread importance neurodegeneration, aging, cancer; however, a structural understanding has been lacking. Rostislavleva et al. provide atomic-resolution insights into structures Vps34-containing required for autophagy, endocytic...
Synergistic activation by heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) and receptor tyrosine kinases distinguishes p110β from other class IA phosphoinositide 3-kinases (PI3Ks). Activation of is specifically implicated in various physiological pathophysiological processes, such as the growth tumors deficient phosphatase tensin homolog deleted chromosome 10 (PTEN). To determine specific contribution GPCR signaling to p110β-dependent functions, we...
Phosphoinositide 3-kinase gamma (PI3Kγ) has profound roles downstream of G-protein-coupled receptors in inflammation, cardiac function, and tumor progression. To gain insight into how the enzyme's activity is shaped by association with its p101 adaptor subunit, lipid membranes, Gβγ heterodimers, we mapped these regulatory interactions using hydrogen-deuterium exchange mass spectrometry. We identify residues both p110γ subunits that contribute critical leading to PI3Kγ activation. Mutating...
Phosphatidylinositol 4-kinases (PI4Ks) and small guanosine triphosphatases (GTPases) are essential for processes that require expansion remodeling of phosphatidylinositol 4-phosphate (PI4P)-containing membranes, including cytokinesis, intracellular development malarial pathogens, replication a wide range RNA viruses. However, the structural basis coordination PI4K, GTPases, their effectors is unknown. Here, we describe structures PI4Kβ (PI4KIIIβ) bound to GTPase Rab11a without with Rab11...
The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel target for malaria, to enter clinical development. In an effort identify next generation of PI4K inhibitors, series optimized improve properties such as solubility and antiplasmodial potency across parasite life cycle, leading 2-aminopyrazine UCT943.
Significance Activated PI3K Delta Syndrome (APDS) is a primary immunodeficiency disease caused by activating mutations in phosphoinositide 3-kinases (PI3Kδ). Activating either the p110δ catalytic or p85α regulatory subunit of PI3Kδ result APDS. Mutations leading to APDS are surprising, as other p85α-activating oncogenic when bound PI3Kα isoform. Using hydrogen–deuterium exchange mass spectrometry, we determined molecular mechanisms which activate and reveal why APDS2 mutant primarily...
Abstract BKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors for treatment cancer, but it interferes as an off-target effect with microtubule polymerization. Here, we developed two chemical derivatives that differ from by only atom. We show these minute changes separate dual activity into discrete PI3K and tubulin inhibitors. Analysis compounds cellular growth arrest phenotypes dynamics suggest antiproliferative mainly due to microtubule-dependent...
Significance Akt is a paradigmatic lipid-activated kinase, which frequently hyperactivated in human cancer. In the absence of PI(3,4,5)P 3 or PI(3,4)P 2 , maintained an inactive conformation by inhibitory interaction between its membrane-binding PH domain and kinase domain. Here, we describe conformational changes associated with binding to leading disruption PH−kinase interface, consequent activation protein kinases. Intriguingly, find that reversal those promotes inactivation phosphatases....
3-phosphoinositide-dependent kinase 1 (PDK1) is an essential serine/threonine protein kinase, which plays a crucial role in cell growth and proliferation. It often referred to as 'master' due its ability activate at least 23 downstream kinases implicated various signaling pathways. In this study, we have elucidated the mechanism of phosphoinositide-driven PDK1 auto-activation. We show that trans-autophosphorylation mediated by PIP