A5067178930- Melanoma and MAPK Pathways
- Protein Tyrosine Phosphatases
- Hemoglobin structure and function
- ATP Synthase and ATPases Research
- Nitric Oxide and Endothelin Effects
- 14-3-3 protein interactions
- Photosynthetic Processes and Mechanisms
- Protein Kinase Regulation and GTPase Signaling
- Cancer Mechanisms and Therapy
- Porphyrin Metabolism and Disorders
- Cytokine Signaling Pathways and Interactions
- Metal-Catalyzed Oxygenation Mechanisms
- Synthesis and biological activity
- Peptidase Inhibition and Analysis
- Computational Drug Discovery Methods
- PI3K/AKT/mTOR signaling in cancer
- Monoclonal and Polyclonal Antibodies Research
- Drug Transport and Resistance Mechanisms
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- CRISPR and Genetic Engineering
- Glycosylation and Glycoproteins Research
- Ubiquitin and proteasome pathways
- Enzyme Structure and Function
- Advanced Electron Microscopy Techniques and Applications
- Innovative Microfluidic and Catalytic Techniques Innovation
Gilead Sciences (United States)
2015-2019
Genentech
2013-2014
Cornell University
2006-2012
Queen Mary University of London
2008-2009
Rutherford Appleton Laboratory
2008-2009
Czech Academy of Sciences, J. Heyrovský Institute of Physical Chemistry
2009
Northwestern University
2009
Albert Einstein College of Medicine
2008
California Institute of Technology
2008
Indian Institute of Technology Bombay
2004
Abstract GS-5734 is a monophosphate prodrug of an adenosine nucleoside analog that showed therapeutic efficacy in non-human primate model Ebola virus infection. It has been administered under compassionate use to two patients, both whom survived, and currently Phase 2 clinical development for treatment disease. Here we report the antiviral activities parent across multiple families, providing evidence support new indications this compound against human viruses significant public health concern.
Energy flow in biological structures often requires submillisecond charge transport over long molecular distances. Kinetics modeling suggests that charge-transfer rates can be greatly enhanced by multistep electron tunneling which redox-active amino acid side chains act as intermediate donors or acceptors. We report transient optical and infrared spectroscopic experiments quantify the extent to an intervening tryptophan residue facilitate transfer between distant metal redox centers a mutant...
Abstract The RAS–RAF pathway is one of the most commonly dysregulated in human cancers 1–3 . Despite decades study, understanding molecular mechanisms underlying dimerization and activation 4 kinase RAF remains limited. Recent structures inactive monomer 5 active dimer 5–8 bound to 14-3-3 9,10 have revealed by which stabilizes both conformations via specific phosphoserine residues. Prior dimerization, protein phosphatase 1 catalytic subunit (PP1C) must dephosphorylate N-terminal (NTpS) 11...
Cancer immunotherapy approaches that elicit immune cell responses, including T and NK cells, have revolutionized the field of oncology. However, immunosuppressive mechanisms restrain activation within solid tumors so additional strategies to augment activity are required.
KRAS, which is mutated in ∼30% of all cancers, activates the RAF-MEK-ERK signaling cascade. CRAF required for growth KRAS mutant lung tumors, but requirement kinase activity unknown. Here, we show that subsets tumors are dependent on growth. Kinase-dead not dimer-defective rescues inhibition, suggesting dimerization required. Quantitative proteomics demonstrates increased levels CRAF:ARAF dimers cells, and depletion both ARAF CRAF-loss phenotype. Mechanistically, causes sustained ERK...
The epidermis is a barrier that prevents water loss while keeping harmful substances from penetrating the host. impermeable cornified layer of stratum corneum maintained by balancing continuous turnover driven epidermal basal cell proliferation, suprabasal differentiation, and corneal shedding. desquamation process tightly regulated balance activities serine proteases Kallikrein-related peptidases (KLK) family their cognate inhibitor lymphoepithelial Kazal type-related (LEKTI), which encoded...
Personalized cancer therapeutics bring directed treatment options to patients based on their tumor's genetic signature. Unfortunately, tumor genomes are remarkably adaptable, and acquired resistance through gene mutation frequently occurs. Identifying mutations that promote within drug-treated patient populations can be cost, resource, time intensive. Accordingly, base editing, enabled by Cas9-deaminase domain fusions, has emerged as a promising approach for rapid, large-scale variant...
AtNOS1/AtNOA1 was identified as a nitric oxide-generating enzyme in plants, but that function has recently been questioned. To resolve issues surrounding AtNOA1 activity, we report the biochemical properties and 2.36 Å resolution crystal structure of bacterial ortholog (YqeH). Geobacillus YqeH fused to putative leader peptide complements growth morphological defects Atnoa1 mutant plants. does not synthesize oxide from l-arginine rather hydrolyzes GTP. The reveals circularly permuted GTPase...
Cryoreduction EPR/ENDOR/step-annealing measurements with substrate complexes of oxy-gsNOS (3; gsNOS is nitric oxide synthase from Geobacillus stearothermophilus) confirm that Compound I (6) the reactive heme species carries out gsNOS-catalyzed (Stage I) oxidation l-arginine to N-hydroxy-l-arginine (NOHA), whereas active in II) NOHA citrulline and HNO/NO− hydroperoxy-ferric form (5). When 3 reduced by tetrahydrobiopterin (BH4), instead an externally supplied electron, resulting BH4+ radical...
Abstract The [Re I (CO) 3 (4,7‐dimethyl‐1,10‐phenanthroline)(histidine‐124)(tryptophan‐122)] complex, denoted (dmp)(W122)], of Pseudomonas aeruginosa azurin behaves as a single photoactive unit that triggers very fast electron transfer (ET) from distant (2 nm) Cu center in the protein. Analysis time‐resolved (ps–μs) IR spectroscopic and kinetics data collected on (dmp)(W122)AzM] (in which M=Zn II , ; Az=azurin) position‐122 tyrosine (Y), phenylalanine (F), lysine (K) mutants, together with...
The Ras-RAF-MEK-ERK signaling axis, commonly mutated in human cancers, is highly regulated to prevent aberrant healthy cells. One of the pathway modulators, 14–3–3, a constitutive dimer, induces RAF dimerization and activation by binding phosphorylated motif C-terminal kinase domain. Recent work has suggested that "DTS" region BRAF necessary for this 14–3–3-mediated activation. We show catalytic activity ATP affinity BRAF:14–3–3 complex insensitive presence or absence DTS, while sites both...
Photoinduced relaxation processes of five structurally characterized Pseudomonas aeruginosa ReI(CO)3(α-diimine)(HisX) (X = 83, 107, 109, 124, 126)CuII azurins have been investigated by time-resolved (ps−ns) IR spectroscopy and emission spectroscopy. Crystal structures reveal the presence Re-azurin dimers trimers that in two cases 124) involve van der Waals interactions between interdigitated diimine aromatic rings. Time-dependent anisotropy measurements confirm proteins aggregate mM...
High-resolution structures of proteins and protein complexes are critical to understanding molecular mechanisms biological processes in the discovery therapeutic molecules. CryoEM has revolutionized structure determination large their complexes, but a vast majority proteins, including that underlie human diseases small (<50 kDa) usually beyond its reach due low signal-to- noise images difficulties particle alignment. Previously reported solutions (structure chaperones), which directly...
Significance Cytokines are proteins that modulate the activity of target cells via activation cell-surface receptors. The trimeric cytokines tumor necrosis factor superfamily typically signal by inducing homotrimerization their cognate We use structural and biophysical approaches to show unique heterotrimeric member Lymphotoxin (LT)α 1 β 2 induces dimerization rather than trimerization LTβ Receptor (LTβR). Cellular signaling assays were used LTβR is sufficient activate intracellular...
The apoprotein of Pseudomonas aeruginosa azurin binds iron(II) to give a 1:1 complex, which has been characterized by electronic absorption, Mössbauer, and NMR spectroscopies, as well X-ray crystallography quantum-chemical computations. Despite potential competition water other coordinating residues, tightly the low-coordinate site. complex does not react with chemical redox agents undergo oxidation or reduction. Spectroscopically calibrated computations show that high-spin in...