A5042019588- Cancer-related Molecular Pathways
- Ubiquitin and proteasome pathways
- Science, Research, and Medicine
- Protein Kinase Regulation and GTPase Signaling
- Enzyme Structure and Function
- Health, Environment, Cognitive Aging
- RNA Research and Splicing
- Biochemical and Molecular Research
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- Virus-based gene therapy research
- Cancer Research and Treatments
- Advanced Electron Microscopy Techniques and Applications
- Machine Learning in Materials Science
- RNA Interference and Gene Delivery
- Autism Spectrum Disorder Research
- Cell death mechanisms and regulation
- Genetics, Aging, and Longevity in Model Organisms
- Immunotherapy and Immune Responses
- RNA modifications and cancer
- Metabolomics and Mass Spectrometry Studies
- vaccines and immunoinformatics approaches
- Cell Image Analysis Techniques
University of California, San Francisco
2019-2024
Howard Hughes Medical Institute
2019-2024
City College of San Francisco
2024
Rapt Therapeutics (United States)
2023
University of California, Santa Cruz
2015-2022
Scripps Research Institute
2011-2012
The p27 protein is a canonical negative regulator of cell proliferation and acts primarily by inhibiting cyclin-dependent kinases (CDKs). Under some circumstances, associated with active CDK4, but no mechanism for activation has been described. We found that p27, when phosphorylated tyrosine kinases, allosterically activated CDK4 in complex cyclin D1 (CDK4-CycD1). Structural biochemical data revealed binding (phosp27) to altered the kinase adenosine triphosphate site promote phosphorylation...
Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and a therapeutic window. The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor G12C K-Ras, sotorasib, provides case in point. KRAS is most frequently mutated proto-oncogene human cancer, yet despite success targeting allele, targeted therapy for other hotspot mutants has not been described. Here we report discovery small molecules covalently target G12S somatic...
KRAS mutations are one of the most common oncogenic drivers in human cancer. While small molecule inhibitors for G12C mutant have been successfully developed, allele-specific inhibition other hotspot mutants remains challenging. Here we report discovery covalent chemical ligands K-Ras(G12R). These bind Switch II pocket and irreversibly react with arginine residue. An X-ray crystal structure reveals an imidazolium condensation product formed between α,β-diketoamide ligand ε- η-nitrogens 12....
K-Ras is the most commonly mutated oncogene in human cancer. The recently approved non-small cell lung cancer drugs sotorasib and adagrasib covalently capture an acquired cysteine K-Ras-G12C mutation lock it a signaling-incompetent state. However, covalent inhibition of G12D, frequent particularly prevalent pancreatic ductal adenocarcinoma, has remained elusive due to lack aspartate-targeting chemistry. Here we present set malolactone-based electrophiles that exploit ring strain crosslink...
The DREAM complex represses cell cycle genes during quiescence through scaffolding MuvB proteins with E2F4/5 and the Rb tumor suppressor paralog p107 or p130. Upon entry, dissociates from p107/p130 recruits B-Myb FoxM1 for up-regulating mitotic gene expression. To understand biochemical mechanisms underpinning function regulation, we investigated structural basis assembly. We identified a sequence in component LIN52 that binds directly to pocket domains of p130 when phosphorylated on DYRK1A...
The transcription factor and tumor suppressor protein p53 is the most frequently mutated inactivated gene in cancer. Mutations result deregulated cell proliferation genomic instability, both hallmarks of There are currently no therapies available that directly target mutant to rescue wild-type function. In this study, we identify covalent compsounds selectively react with somatic cysteine Y220C restore thermal stability. cancer, yet therapeutics date first allele-specific compound reacts...
Summary Translating high-confidence (hc) autism spectrum disorder (ASD) genes into viable treatment targets remains elusive. We constructed a foundational protein-protein interaction (PPI) network in HEK293T cells involving 100 hcASD risk genes, revealing over 1,800 PPIs (87% novel). Interactors, expressed the human brain and enriched for ASD but not schizophrenia genetic risk, converged on protein complexes involved neurogenesis, tubulin biology, transcriptional regulation, chromatin...
The chromatin architecture in promoters is thought to regulate gene expression, but it remains uncertain how most transcription factors (TFs) impact nucleosome position. MuvB TF complex regulates cell-cycle dependent gene-expression and critical for differentiation proliferation during development cancer. can both positively negatively the structure of its biochemical function are poorly understood. Here we determine overall assembly crystal a subcomplex repression. We find that subunits...
The MuvB transcriptional regulatory complex, which controls cell-cycle-dependent gene expression, cooperates with B-Myb to activate genes required for the G2 and M phases of cell cycle. We have identified domain in that is essential assembly Myb–MuvB (MMB) complex. determined a crystal structure reveals how this binds through adaptor protein LIN52 scaffold LIN9. biochemical analysis provide an understanding oncogenic recruited regulate cell-cycle progression, MMB interface presents potential...
We describe an inexpensive and efficient method for generating functional pools of Dicer-substrate small interfering RNAs (siRNAs) in a single reaction tube. The exploits highly active form the enzyme Dicer from Giardia lamblia, which is capable accurately processing double-stranded RNA (dsRNA) into 25–27 nt during vitro transcription. produced function as substrates human induce gene silencing with potency equivalent to traditional siRNAs when introduced mammalian cells. overall simple, can...
The five-protein MuvB core complex is highly conserved in animals. This nuclear interacts with RB-family tumor suppressor proteins and E2F-DP transcription factors to form DREAM complexes that repress genes regulate cell cycle progression fate. also Myb family oncoproteins the Myb-MuvB activate many of same genes. We show animal-type are present Bilateria, Cnidaria Placozoa, latter including simplest known animal species. However, bilaterian nematode worms lost their hundreds millions years...
Protein properties and interactions have been widely investigated by using external labels. However, the micromolar sensitivity of current dyes limits their applicability due to high material consumption assay cost. In response this challenge, we synthesized a series cyanine5 (Cy5) dye-based quencher molecules develop an dye technique probe proteins at nanomolar protein level in high-throughput one-step format. Several families Cy5 quenchers with ring and/or side-chain modifications were...
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B-Myb is a highly conserved member of the vertebrate Myb family transcription factors that plays critical role in cell-cycle progression and proliferation. proteins activate Myb-dependent promoters by interacting specifically with Myb-binding site (MBS) sequences using their DNA-binding domain (DBD). Transactivation MBS repressed its negative regulatory (NRD), phosphorylation NRD Cdk2-CyclinA relieves repression to B-Myb–dependent promoters. However, structural mechanisms underlying...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common cancer. A high percentage (>90%) of PDAC patients harbor KRAS mutations, with majority expressing K-Ras(G12D) missense mutation protein. Despite extensive drug discovery efforts across academia and industry, there are no approved drugs directly targeting oncogenic in a mutant-selective manner. We have developed series small molecules that form covalent bonds mutant protein at its site. The lead molecule...
Abstract K-Ras is the most commonly mutated oncogene in human cancer, yet direct small-molecule targeting of mutants has been mostly unsuccessful until recently. The discovery an allosteric pocket under Switch-II with covalent cysteine-crosslinking molecules allowed for development targeted therapies that selectively engage highly reactive acquired cysteine K-Ras(G12C) mutation without affecting wild-type protein. Sotorasib and adagrasib, two advanced Pocket inhibitors, have received FDA...
Abstract The loss of cell cycle control is the most recognized trait cancer cells. ability cells to exit has recently been shown be dependent upon a large multi-protein repressor complex called DREAM. This represses expression all genes during reversible exit. In cycling cells, DREAM disassembled and some associated proteins form new promote gene expression. These that can act together both as repressors activators are MuvB core. core interacts with B-Myb S phase late activator MMB its...
<div>Abstract<p>The transcription factor and tumor suppressor protein p53 is the most frequently mutated inactivated gene in cancer. Mutations result deregulated cell proliferation genomic instability, both hallmarks of There are currently no therapies available that directly target mutant to rescue wild-type function. In this study, we identify covalent compsounds selectively react with somatic cysteine Y220C restore thermal stability.</p>Significance:<p>The cancer,...
<p>Supplementary Figure S1: p53 hotspot mutations (A) Crystal structure of bound to DNA PDB 1TUP with structural and DNA-contact highlighted. (B) Frequency out total alterations based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. (C) The urea-denaturation free energy values from stabilizing plotted previous studies (7). (D) SDS-PAGE recombinant protein used in study stained Coomassie blue.</p>