A5089941665- Click Chemistry and Applications
- Genomics and Chromatin Dynamics
- Protein Degradation and Inhibitors
- Chemical Synthesis and Analysis
- Ubiquitin and proteasome pathways
- RNA and protein synthesis mechanisms
- Protein Structure and Dynamics
- Asymmetric Synthesis and Catalysis
- Receptor Mechanisms and Signaling
- Cancer-related gene regulation
- Synthetic Organic Chemistry Methods
- Plant biochemistry and biosynthesis
- RNA Research and Splicing
- Chromatin Remodeling and Cancer
- NF-κB Signaling Pathways
- Monoclonal and Polyclonal Antibodies Research
- Microbial Natural Products and Biosynthesis
- Biochemical Analysis and Sensing Techniques
- Biotin and Related Studies
- Natural product bioactivities and synthesis
- Synthesis and Catalytic Reactions
- Protein Kinase Regulation and GTPase Signaling
- DNA and Nucleic Acid Chemistry
- Phytochemistry and Biological Activities
- Phosphorus compounds and reactions
University of Michigan
2015-2024
Washtenaw Community College
2014-2024
Michigan United
2008-2022
Ann Arbor Center for Independent Living
2003-2018
Life Science Institute
2015
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
2013
University of Maryland, Baltimore
2013
The Ohio State University Wexner Medical Center
2013
Institute of Medicinal Plant Development
2011
Salk Institute for Biological Studies
2009
Eukaryotic transcriptional activators are minimally comprised of a DNA binding domain and separable activation domain; most activator proteins also bear dimerization module. We have replaced these protein modules with synthetic counterparts to create artificial transcription factors. One these, at 4.2 kDa, mediates high levels site-specific in vitro . This molecule contains sequence-specific polyamide place the typical region nonprotein linker usual peptide. Thus our activating region,...
Like many coactivators, the GACKIX domain of master coactivator CBP/p300 recognizes transcriptional activators diverse sequence composition via dynamic binding surfaces. The conformational dynamics that underlie its function also render it especially challenging for structural characterization. We have found ligand discovery strategy Tethering is an effective method identifying small-molecule fragments stabilize domain, enabling first time crystallographic characterization this important...
Pharmacological manipulation of the melanocortin-3 receptor bidirectionally controls feeding, providing a therapeutic target for eating disorders.
Abstract For see ChemInform in Full Text.
We have demonstrated that the high yields and selectivities of 1,3-dipolar cycloadditions can be translated into facile stereoselective syntheses a diverse array β-amino acids, key components bioactive natural products, β-lactams, peptidomimetics. Simply by selecting different combinations three readily available starting materials (an oxime, chiral allylic alcohol, nucleophile), we used reaction sequence to prepare four acid structural types with variety substitution patterns in good...
Artificial transcriptional activators are excellent tools for studying the mechanistic details of regulation. Furthermore, as correlation between a wide range human diseases and misregulated transcription becomes increasingly evident, such molecules may in long run serve basis transcription-based therapeutic agents. The greatest challenge this arena has been discovery organic that functional mimics activation domains, sequences natural proteins participate variety protein−protein...
The conformationally dynamic binding surfaces of transcription complexes present a particular challenge for ligand discovery and characterization. In the case KIX domain master coactivator CBP/p300, few small molecules have been reported that target its two allosterically regulated sites despite important roles plays in processes ranging from memory formation to hematopoiesis. Taking advantage enrichment aromatic amino acids at protein interfaces, here we show incorporation six 19F-labeled...
The kinase-inducible domain interacting (KIX) of the CREB binding protein (CBP) is capable simultaneously two intrinsically disordered transcription factors, such as mixed-lineage leukemia (MLL) and c-Myb peptides, at isolated interaction sites. In vitro, affinity for approximately doubled when KIX in complex with MLL, which suggests a positive cooperative mechanism, MLL also slightly increased first bound by c-Myb. Expanding scope recent NMR computational studies, we explore allosteric...
Conformationally heterogenous or "fuzzy" proteins have often been described as lacking specificity in binding and function. The activation domains, for example, of transcriptional activators were labeled negative noodles, with little structure specificity. However, emerging data illustrates that the opposite is true: conformational heterogeneity enables context-specific function to emerge response changing cellular conditions and, furthermore, allows a single structural motif be used...
Small molecules that reconstitute the binding mode(s) of a protein and in doing so elicit programmed functional response offer considerable advantages control complex biological processes. The development challenges such are significant, however. Many protein–protein interactions require multiple points contact over relatively large surface areas. More significantly, several modes can be superimposed upon single sequence within protein, true small molecule replacement must preprogrammed for...
Capturing a coactivator, naturally: The natural products sekikaic acid and lobaric acid, isolated after high-throughput screen of structurally diverse extract collection, effectively target the dynamic binding interfaces GACKIX domain coactivator CBP/p300 (see structure). These molecules are most effective inhibitors yet described uniquely selective for this domain. Detailed facts importance to specialist readers published as "Supporting Information". Such documents peer-reviewed, but not...
A key functional event in eukaryotic gene activation is the formation of dynamic protein-protein interaction networks between transcriptional activators and coactivators. Seemingly incongruent with tight regulation transcription, many biochemical biophysical studies suggest that use nonspecific hydrophobic and/or electrostatic interactions to bind coactivators, few if any specific contacts. Here a mechanistic dissection set representative activator•coactivator complexes, comprised ETV/PEA3...
The COVID-19 pandemic has highlighted the need for new antiviral approaches because many of currently approved drugs have proven ineffective against mitigating SARS-CoV-2 infections. host transmembrane serine protease TMPRSS2 is a promising target it plays role in priming spike protein before viral entry occurs most virulent variants. Further, no established physiological role, thereby increasing its attractiveness as agents. Here, we utilize virtual screening to curate large libraries into...
The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thus tonically suppresses multiple circuits involved in feeding behavior energy homeostasis. Here, we examined the role of MC3R melanocortin system regulating response to various anorexigenic agents. genetic deletion or pharmacological inhibition MC3R, subthreshold doses an MC4R agonist, improved dose responsiveness glucagon-like peptide 1 (GLP1) agonists, as assayed by food...