A5065806766- Hippo pathway signaling and YAP/TAZ
- RNA Research and Splicing
- RNA Interference and Gene Delivery
- RNA and protein synthesis mechanisms
- Antibiotic Resistance in Bacteria
- Ubiquitin and proteasome pathways
- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Glycosylation and Glycoproteins Research
- Peptidase Inhibition and Analysis
- Enzyme Structure and Function
- Drug Transport and Resistance Mechanisms
- Lipid metabolism and biosynthesis
- Genomics and Phylogenetic Studies
- RNA regulation and disease
- Microtubule and mitosis dynamics
- MicroRNA in disease regulation
- Cellular Mechanics and Interactions
- Bacterial Genetics and Biotechnology
- Ion Transport and Channel Regulation
- Cellular transport and secretion
- Multiple Myeloma Research and Treatments
- Lipoproteins and Cardiovascular Health
- Sleep and Wakefulness Research
- Bacterial Identification and Susceptibility Testing
Merck & Co., Inc., Rahway, NJ, USA (United States)
2022-2023
Genentech
2015
University of California, Berkeley
2009-2014
Lawrence Berkeley National Laboratory
2013
Institute of Agrifood Research and Technology
2009
Abstract The Hippo pathway is a key growth control that conserved across species. downstream effectors of the pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation survival. Based on premise sustained interactions between YAP/TAZ TEADs enhanced associate domain) central their transcriptional activities, we discovered potent small-molecule inhibitor (SMI), GNE-7883, allosterically blocks...
During RNA interference and related gene regulatory pathways, the endonuclease Dicer cleaves precursor molecules to produce microRNAs (miRNAs) short interfering RNAs (siRNAs). Human cells encode a single enzyme that can associate with two different double-stranded (dsRNA)-binding proteins, protein activator of PKR (PACT) trans-activation response RNA-binding (TRBP). However, functional redundancy or differentiation PACT TRBP in miRNA siRNA biogenesis is not well understood. Using...
Small RNAs guide RNA-induced silencing complexes (RISCs) to bind cognate mRNA transcripts and trigger of protein expression during RNA interference (RNAi) in eukaryotes. A fundamental aspect this process is the asymmetric loading one strand a short interfering (siRNA) or microRNA (miRNA) duplex onto RISCs for correct target recognition. Here, we use reconstituted system determine extent which core components human RNAi machinery contribute selection. We show that Argonaute2 (Ago2),...
The transcriptional enhanced associate domain (TEAD) family of transcription factors serves as the receptors for downstream effectors Hippo pathway, YAP and TAZ, to upregulate expression multiple genes involved in cellular proliferation survival. Recent work identified TEAD S-palmitoylation critical protein stability activity lipid tail extends into a hydrophobic core protein. Here, we report identification characterization potent small molecule that binds pocket (LP) disrupts...
The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target much recent interest in cancer and immune system regulation. A co-crystal structure ligand-efficient screening hit CBP guided initial design targeting LPF shelf, ZA loop, acetylated lysine binding regions. Structure-activity relationship studies allowed us to identify more potent analogue. Optimization permeability microsomal stability subsequent improvement mouse hepatocyte afforded 59 (GNE-272,...
Significance Lipoprotein biosynthesis is crucial for Gram-negative bacterial viability and involves the activities of three essential integral membrane proteins embedded in inner (Lgt, LspA, Lnt). These enzymes function sequentially to produce mature triacylated lipoproteins, many which are then transported outer membrane. Lnt responsible catalyzing addition palmitate N terminus diacylated apolipoproteins. Despite a number studies that have biochemically characterized Escherichia coli Lnt,...
Pim kinases have been targets of interest for a number therapeutic areas. Evidence durable single-agent efficacy in human clinical trials validated kinase inhibition as promising approach multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), potent, orally bioavailable, and well tolerated pan-Pim inhibitor that proved efficacious RPMI8226 MM.1S xenograft mouse models has evaluated an early development candidate.
Lipoprotein diacylglyceryl transferase (Lgt) catalyzes the first step in biogenesis of Gram-negative bacterial lipoproteins which play crucial roles growth and pathogenesis. We demonstrate that Lgt depletion a clinical uropathogenic Escherichia coli strain leads to permeabilization outer membrane increased sensitivity serum killing antibiotics. Importantly, we identify G2824 as first-described inhibitor potently inhibits biochemical activity vitro is bactericidal against wild-type...
Unlike classical voltage-gated sodium (NaV) channels, NaX has been characterized as a voltage-insensitive, tetrodotoxin-resistant, (Na+)-activated channel involved in regulating Na+ homeostasis. However, remains refractory to functional characterization traditional heterologous systems. Here, gain insight into its atypical physiology, we determine structures of the human complex with auxiliary β3-subunit. reveals structural alterations within selectivity filter, voltage sensor-like domains,...
Abstract Coronaviruses have been the causative agent of three epidemics and pandemics in past two decades, including ongoing COVID-19 pandemic. A broadly-neutralizing coronavirus therapeutic is desirable not only to prevent treat COVID-19, but also provide protection for high-risk populations against future emergent coronaviruses. As all coronaviruses use spike proteins on viral surface enter host cells, these share sequence structural homology, we set out discover cross-reactive biologic...
Despite increasing evidence suggesting that antibiotic heteroresistance can lead to treatment failure, the significance of this phenomena in clinic is not well understood, because many clinical susceptibility testing approaches lack resolution needed reliably classify heteroresistant strains. Here we present G0790, a new globomycin analog and potent inhibitor Escherichia coli type II signal peptidase LspA. We demonstrate addition previously known mechanisms resistance LspA inhibitors,...
Partitioning duplicated chromosomes equally between daughter cells is a microtubule-mediated process essential to eukaryotic life. A multi-protein machine, the kinetochore, drives chromosome segregation by coupling dynamic microtubule tips, even as tips grow and shrink through gain loss of subunits. The kinetochore must harness, transmit, sense mitotic forces, lack tension signals incorrect chromosome-microtubule attachment precipitates error correction mechanisms. But though field has...
Acoustic droplet ejection (ADE) enables crystallization experiments at the low-nanoliter scale, resulting in rapid vapor diffusion equilibration dynamics and efficient reagent usage empirical discovery of structure-enabling protein conditions. We extend our validation this technology applied to diverse physicochemical property space aqueous reagents where dynamic fluid analysis coupled ADE aids accurate precise dispensations. Addition seed stocks, chemical additives, or small-molecule...
The Hippo pathway is among the most frequently altered key signaling pathways in cancer. TEAD1-4 are essential transcription factors and downstream effectors pathway. Here we identified RNF146 as a ubiquitin ligase (E3) that can catalyze TEAD ubiquitination negatively regulate their function cells. We show this of TEADs governed by PARylation state validated genetic interaction between cancer cell lines model organism Drosophila melanogaster. Furthermore, demonstrate pharmacologically...
The Hippo pathway is among the most frequently altered key signaling pathways in cancer. TEAD1-4 are essential transcription factors and downstream effectors human cells. Here, we identified RNF146 as a ubiquitin ligase (E3) of TEADs, which negatively regulates their stability cells through proteasome-mediated degradation. We show that RNF146-mediated TEAD ubiquitination dependent on PARylation state. further validated genetic interaction between cancer cell lines model organism Drosophila...
Chromosomal deletions and duplications, which result in halving or doubling of copy number a block genes, are an important source variation between individuals. Phenotypic effects commonly observed, but on sensitivity to volatile anesthetics have not been assessed any organism.The potency with halothane depresses the righting reflex fruit flies was measured congenic Drosophila strains, each heterozygous for deletion average size 400 kb. Over 200 strains were examined, thereby scanning...