A5087413939- RNA modifications and cancer
- RNA Research and Splicing
- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Cancer Genomics and Diagnostics
- Cancer-related Molecular Pathways
- Protein Degradation and Inhibitors
- Enzyme Structure and Function
- RNA and protein synthesis mechanisms
- Ferroptosis and cancer prognosis
- Monoclonal and Polyclonal Antibodies Research
- Cancer, Lipids, and Metabolism
- Microbial Natural Products and Biosynthesis
- Epigenetics and DNA Methylation
- Ubiquitin and proteasome pathways
- Glycosylation and Glycoproteins Research
- Chemical Synthesis and Analysis
- Mass Spectrometry Techniques and Applications
- Bioinformatics and Genomic Networks
- Viral Infectious Diseases and Gene Expression in Insects
- Transgenic Plants and Applications
- Cancer-related molecular mechanisms research
- Toxin Mechanisms and Immunotoxins
- Multiple Myeloma Research and Treatments
- Cancer Research and Treatments
Fox Chase Cancer Center
2016-2025
University of Alabama at Birmingham
2024
Nova Southeastern University
2024
Temple University
2022-2024
California University of Pennsylvania
2024
University of Kansas
2009-2017
High Throughput Biology (United States)
2015
Howard Hughes Medical Institute
2006-2011
University of Washington
2006-2011
Seattle University
2011
Based on the crystal structure of cross-β spine formed by peptide NNQQNY, we have developed a computational approach for identifying those segments amyloidogenic proteins that themselves can form amyloid-like fibrils. The builds experiments showing hexapeptides are sufficient forming Each six-residue protein interest is mapped onto an ensemble templates, or 3D profile, generated from NNQQNY small displacements one two intermeshed β-sheets relative to other. energy each mapping sequence...
Topology has been shown to be an important determinant of many features protein folding; however, the delineation sequence effects on folding remains obscure. Furthermore, differentiation between two influences proves difficult due their intimate relationship. To investigate effect in absence significant topological differences, we examined mechanisms segment B1 peptostreptococcal L and streptococcal G. These proteins share same highly symmetrical topology. Despite this symmetry, neither...
With the recent explosion in size of libraries available for screening, virtual screening is positioned to assume a more prominent role early drug discovery's search active chemical matter. In typical screens, however, only about 12% top-scoring compounds actually show activity when tested biochemical assays. We argue that most scoring functions used this task have been developed with insufficient thoughtfulness into datasets on which they are trained and tested, leading overly simplistic...
Proteolysis-targeting chimaeras (PROTACs) are molecules that combine a target-binding warhead with an E3 ligase-recruiting moiety; by drawing the target protein into ternary complex ligase, PROTACs induce degradation. While hold exciting potential as chemical probes and therapeutic agents, development of PROTAC typically requires synthesis numerous analogs to thoroughly explore variations on linker; without extensive trial error, it is unclear how link two protein-recruiting moieties promote...
Musashi‐1 (MSI1) is an RNA‐binding protein that acts as a translation activator or repressor of target mRNAs. The best‐characterized MSI1 Numb mRNA, whose encoded negatively regulates Notch signaling. Additional targets include the mRNAs for tumor suppressor APC Wnt signaling and cyclin‐dependent kinase inhibitor P21WAF−1. We hypothesized increased expression NUMB, P21 APC, through inhibition activity might be effective way to simultaneously downregulate signaling, thus blocking growth broad...
Differential scanning fluorimetry (DSF), also known as ThermoFluor or Thermal Shift Assay, has become a commonly-used approach for detecting protein-ligand interactions, particularly in the context of fragment screening. Upon binding to folded protein, most ligands stabilize protein; thus, observing an increase temperature at which protein unfolds function ligand concentration can serve evidence direct interaction. While experimental protocols this assay are well-developed, it is not...
Abstract Patients diagnosed with metastatic breast cancer have a dismal 5-year survival rate of only 24%. The RNA-binding protein Hu antigen R (HuR) is upregulated in cancer, and elevated cytoplasmic HuR correlates high-grade tumors poor clinical outcome cancer. promotes tumorigenesis by regulating numerous proto-oncogenes, growth factors, cytokines that support major tumor hallmarks including invasion metastasis. Here, we report inhibitor KH-3, which potently suppresses cell invasion....
The mechanism of formation β-sheets is great importance because the significant role such structures in initiation and propagation amyloid diseases. In this study we examine folding a series three-stranded antiparallel known as WW domains. Whereas other domains have been shown to fold with single-exponential kinetics, domain from murine formin-binding protein 28 has recently biphasic kinetics. By using combination kinetics thermodynamics characterize simple model for protein, origins found...
Despite intense interest and considerable effort via high-throughput screening, there are few examples of small molecules that directly inhibit protein-protein interactions. This suggests many protein interaction surfaces may not be intrinsically "druggable" by molecules, elevates in importance the successful as model systems for improving our fundamental understanding druggability. Here we describe an approach exploring fluctuations enriched conformations containing surface pockets suitable...
Natural products have served as an inspiration to scientists both for their complex three-dimensional architecture and exquisite biological activity. Promysalin is one such Pseudomonad secondary metabolite that exhibits narrow-spectrum antibacterial activity, originally isolated from the rhizosphere. We herein utilize affinity-based protein profiling (AfBPP) identify succinate dehydrogenase (Sdh) target of natural product. The was further validated in silico, vitro, vivo, through selection,...
Protein–protein interactions play important roles in virtually all cellular processes, making them enticing targets for modulation by small-molecule therapeutics: specific examples have been well validated diseases ranging from cancer and autoimmune disorders, to bacterial viral infections. Despite several notable successes, however, overall these remain a very challenging target class. Protein interaction sites are especially computational approaches, because the protein surface often...
The RNA-binding protein Hu antigen R (HuR) binds to AU-rich elements (ARE) in the 3'-untranslated region (UTR) of target mRNAs. HuR-ARE interactions stabilize many oncogenic mRNAs that play important roles tumorigenesis. Thus, small molecules interfere with interaction could potentially inhibit cancer cell growth and progression. Using a fluorescence polarization (FP) competition assay, we identified compound azaphilone-9 (AZA-9) derived from fungal natural product asperbenzaldehyde, HuR...