A5062118468- Melanoma and MAPK Pathways
- Synthesis and biological activity
- Colorectal Cancer Treatments and Studies
- Protein Kinase Regulation and GTPase Signaling
- RNA and protein synthesis mechanisms
- Cancer Mechanisms and Therapy
- Photosynthetic Processes and Mechanisms
- Bacteriophages and microbial interactions
- Enzyme Structure and Function
- Adenosine and Purinergic Signaling
- Cellular transport and secretion
- DNA and Nucleic Acid Chemistry
- Protein Structure and Dynamics
- Receptor Mechanisms and Signaling
- Glycosylation and Glycoproteins Research
- ATP Synthase and ATPases Research
- Neuroscience and Neuropharmacology Research
- Advanced biosensing and bioanalysis techniques
- Biochemical and Molecular Research
- Carbohydrate Chemistry and Synthesis
- Galectins and Cancer Biology
- Chemical Synthesis and Analysis
- Plant Virus Research Studies
- Endoplasmic Reticulum Stress and Disease
- Ion channel regulation and function
Pfizer (United States)
2024
University of Montana
2011-2022
National University of Singapore
2014
Cheng Ching Hospital
2012
University of Regensburg
2009
Institute of Pharmacology
2009
Medical College of Wisconsin
2009
Medizinische Hochschule Hannover
2009
Advanced Neural Dynamics (United States)
2009
University of Kansas
2009
Specimens below 50 kDa have generally been considered too small to be analyzed by single-particle cryo-electron microscopy (cryo-EM). The high flexibility of pure RNAs makes it difficult obtain high-resolution structures cryo-EM. In bacteria, riboswitches regulate sulfur metabolism through binding the S-adenosylmethionine (SAM) ligand and offer compelling targets for new antibiotics. SAM-I, SAM-I/IV, SAM-IV are three most commonly found SAM riboswitches, but structure is still unknown. Here,...
Significance Cytochrome c is essential to two important biochemical pathways, the electron transport chain and intrinsic pathway of apoptosis. The heme crevice loop, which provides Met80 ligand cofactor, most highly conserved segment cytochrome sequence. dynamics this loop are likely for both functions. -mediated peroxidation cardiolipin in inner mitochondrial membrane an early signal We show that mutation trimethyllysine 72 alanine yeast iso-1-cytochrome allows formation a conformer protein...
Mammals express nine membranous adenylyl cyclase isoforms (ACs 1–9), a structurally related soluble guanylyl (sGC) and AC (sAC). Moreover, Bacillus anthracis pertussis produce the toxins, edema factor (EF), toxin (ACT), respectively. 2′(3′)-O-(N-methylanthraniloyl)-guanosine 5′-[γ-thio]triphosphate is potent competitive inhibitor of in S49 lymphoma cell membranes. These data prompted us to study systematically effects 24 nucleotides on Sf9 insect membranes, ACs 1, 2, 5, 6, expressed...
Adenylyl cyclase (AC) isoforms 1 to 9 are differentially expressed in tissues and constitute an interesting drug target. ACs 8 activated by the diterpene, forskolin (FS). It is unfortunate that there a paucity of AC isoform-selective activators. To develop such compounds, understanding structure/activity relationships diterpenes necessary. Therefore, we examined effects FS nine analogs on 1, 2, 5 <i>Spodoptera frugiperda</i> insect cells. Diterpenes showed highest potencies at AC1 lowest...
The c-MYC oncogene mediates multiple tumor cell survival pathways and is dysregulated or overexpressed in the majority of human cancers. NHE III1 region promoter forms a DNA quadruplex. Stabilization this structure with small molecules has been shown to reduce expression c-MYC, targeting quadruplex become an emerging strategy for development antitumor compounds. Previous solution NMR studies have assigned major conformer topology important target, however, regions outside G-quartet core were...
Prokaryotes and viruses have fought a long battle against each other. use CRISPR–Cas-mediated adaptive immunity, while conversely, evolve multiple anti-CRISPR (Acr) proteins to defeat these CRISPR–Cas systems. The type I-F system in Pseudomonas aeruginosa requires the crRNA-guided surveillance complex (Csy complex) recognize invading DNA. Although some Acr Csy been reported, other relevant still need studies understand their mechanisms. Here, we obtain three structures of previously...
RAF inhibitors have transformed treatment for patients with BRAFV600-mutant cancers, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAFV600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer are a narrow therapeutic index. PF-07799933 (ARRY-440) brain-penetrant, selective, pan-mutant BRAF inhibitor. inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, spared wild-type signaling. ±...
Membrane-bound mammalian adenylyl cyclase (mAC) catalyzes the synthesis of intracellular cyclic AMP from ATP and is activated by stimulatory G protein α subunits (Gα<sub>s</sub>) forskolin (FSK). mACs are inhibited with high potency 2 ′(3′)-<i>O</i>-(<i>N</i>-methylanthraniloyl) (MANT)-substituted nucleotides. In this study, crystal structures complex between Gα<sub>s</sub>·GTPγS catalytic C1 C2 domains type V II mAC (VC1·IIC2), bound to FSK either MANT-GTP·Mg<sup>2+</sup> or...
Type V and VI mammalian adenylyl cyclases (AC5, AC6) are inhibited by Ca(2+) at both sub- supramicromolar concentration. This inhibition may provide feedback in situations where cAMP promotes opening of channels, allowing fine control cardiac contraction rhythmicity tissue AC5 AC6 predominate. inhibits the soluble AC core composed C1 domain (VC1) C2 AC2 (IIC2). As observed for holo-AC5, is biphasic, showing "high-affinity" (K(i) = approximately 0.4 microM) "low-affinity" 100 modes...
NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA comprise two glycine-binding GluN1 and glutamate-binding GluN2 subunits (GluN2A-D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive antagonists, of which ST3 has a binding affinity 52 nM at GluN1/2A 782 GluN1/2B receptors. This 15-fold preference for over is...
Cytochrome c can acquire peroxidase activity when it binds to cardiolipin in mitochondrial membranes. The resulting oxygenation of by cytochrome provides an early signal for the onset apoptosis. structure this enzyme–substrate complex is a matter considerable debate. We present three structures at 1.7–2.0 Å resolution domain-swapped dimer yeast iso-1-cytochrome with detergents, CYMAL-5, CYMAL-6, and ω-undecylenyl-β-d-maltopyranoside, bound channel that places hydrocarbon moieties these...
Human gastric pathogen Helicobacter pylori ( H. ) is the primary risk factor for cancer and one of most prevalent carcinogenic infectious agents. Vacuolating cytotoxin A (VacA) a key virulence secreted by induces multiple cellular responses. Although structural functional studies VacA have been extensively performed, high-resolution structure full-length protomer molecular basis its oligomerization are still unknown. Here, we use cryoelectron microscopy to resolve 10 structures assemblies,...
Membrane adenylyl cyclases (mACs) play an important role in signal transduction and are therefore potential drug targets. Earlier, we identified 2′,3′-<i>O</i>-(<i>N</i>-methylanthraniloyl) (MANT)-substituted purine nucleotides as a novel class of highly potent competitive mAC inhibitors (<i>K<sub>i</sub></i> values the 10 nM range). MANT discriminate among various isoforms through differential interactions with binding pocket localized at interface between C1 C2 domains mAC. In this study,...
The tip of the root is covered by a thimble-shaped cap that site perception and transduction for many environmental stimuli. Until now, little was known about how rice (Oryza sativa) develops functions to regulate adaptive behavior root. To address this, we examined formation during embryogenesis characterized anatomy structure radicle cap. We further investigated role quiescent center in de novo origin At molecular level, found shoot-derived auxin absolutely needed trigger regeneration when...
We test the hypothesis that Lys72 suppresses intrinsic peroxidase activity of human cytochrome c, as observed previously for yeast iso-1-cytochrome c [McClelland, L. J., et al. (2014) Proc. Natl. Acad. Sci. U. S. A. 111, 6648–6653]. A 1.25 Å X-ray structure K72A shows mutation minimally affects structure. Guanidine hydrochloride denaturation demonstrates increases global stability by 0.5 kcal/mol. The also apparent pKa alkaline transition, a measure heme crevice, unit. Consistent with...
Abstract Ric-8A is a cytosolic Guanine Nucleotide exchange Factor (GEF) that activates heterotrimeric G protein alpha subunits (Gα) and serves as an essential Gα chaperone. Mechanisms by which catalyzes these activities, are stimulated Casein Kinase II phosphorylation, unknown. We report the structure of nanobody-stabilized complex nucleotide-free bound to phosphorylated at near atomic resolution cryo-electron microscopy X-ray crystallography. The mechanism GEF activity differs considerably...
HER2 overexpression and amplification have been identified as oncogenic drivers, the development of therapies to treat tumors harboring these markers has received considerable attention. Activation signaling subsequent cell growth can also be induced by mutations, including common YVMA insertion in exon 20 within kinase domain. Enhertu is currently only approved treatment for mutant NSCLC. TKIs tested this space suffered from off-target activity, primarily due EGFR
Adenylyl cyclases (ACs) catalyze the conversion of ATP into second messenger cAMP and play a key role in signal transduction. In recent study (<i>Mol Pharmacol</i><b>70:</b>878–886, 2006), we reported that 2′,3′-<i>O</i>-(2,4,6-trinitrophenyl)-substituted nucleoside 5′-triphosphates (TNP-NTPs) are potent inhibitors (<i>K</i><sub>i</sub> values 10 nM range) purified catalytic subunits VC1 IIC2 membranous AC (mAC). The crystal structure VC1:IIC2 complex with TNP-ATP revealed nucleotide binds...