A5038366026- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Cancer-related gene regulation
- RNA modifications and cancer
- Protein Degradation and Inhibitors
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Monoclonal and Polyclonal Antibodies Research
- Cell death mechanisms and regulation
- Chemical Synthesis and Analysis
- Criminal Justice and Corrections Analysis
- European Criminal Justice and Data Protection
- Ubiquitin and proteasome pathways
- Histone Deacetylase Inhibitors Research
- Peptidase Inhibition and Analysis
- HIV/AIDS drug development and treatment
- Crime Patterns and Interventions
- Click Chemistry and Applications
- RNA Interference and Gene Delivery
- Advanced biosensing and bioanalysis techniques
- Cancer Mechanisms and Therapy
- Crystallography and molecular interactions
- Signaling Pathways in Disease
- ATP Synthase and ATPases Research
- Cancer therapeutics and mechanisms
University of North Carolina at Chapel Hill
2015-2024
University of North Carolina Health Care
2021-2024
Jagiellonian University
2004-2022
Institute of Molecular Biology and Biophysics
1998-2021
Instytut Farmaceutyczny
1993-2018
High Throughput Biology (United States)
2016
Frederick National Laboratory for Cancer Research
2003-2011
National Institutes of Health
2004-2011
National Cancer Institute
2004-2011
Wayne State University
2005-2009
Potent, specific, non-peptide small-molecule inhibitors of the MDM2-p53 interaction were successfully designed. The most potent inhibitor (MI-63) has a K(i) value 3 nM binding to MDM2 and greater than 10,000-fold selectivity over Bcl-2/Bcl-xL proteins. MI-63 is highly effective in activation p53 function inhibition cell growth cancer cells with wild-type status. excellent specificity deleted shows minimal toxicity normal cells.
A successful structure-based design of a class non-peptide small-molecule MDM2 inhibitors targeting the p53-MDM2 protein-protein interaction is reported. The most potent compound 1d binds to protein with Ki value 86 nM and 18 times more than natural p53 peptide (residues 16-27). Compound in inhibition cell growth LNCaP prostate cancer cells wild-type shows only weak activity PC-3 deleted p53. Importantly, has minimal toxicity normal epithelial cells. Our studies provide convincing example...
Data from the Encyclopedia of DNA Elements (ENCODE) project show over 9640 human genome loci classified as long noncoding RNAs (lncRNAs), yet only ∼100 have been deeply characterized to determine their role in cell. To measure protein-coding output these RNAs, we jointly analyzed two recent data sets produced ENCODE project: tandem mass spectrometry (MS/MS) mapping expressed peptides encoding genomic loci, and RNA-seq generated by polyA+ polyA− fractions cell lines K562 GM12878. We used...
Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized 'codes' are read by specialized regions (reader domains) chromatin-associated proteins (CAPs) to regulate downstream function. Substantial effort made define [CAP: histone PTM] specificities, and thus decipher the code guide epigenetic therapies. However, this largely done using reductive approach of isolated reader domains peptides, which cannot...
<b>Objective: </b> To determine the validity and reliability of Charcot-Marie-Tooth disease (CMT) neuropathy score (CMTNS) in patients with inherited neuropathy. <b>Background: Natural history studies potential treatment trials for various forms CMT are limited by lack quantitative methodologies to monitor progression. Most cases can be considered length-dependent axonal neuropathies because disability even demyelinating correlates degeneration. The total (TNS) is a validated composite...
A structure-based approach was employed to design a new class of small-molecule inhibitors Bcl-2. The most potent compound 5 (TW-37) binds Bcl-2 with Ki value 290 nM and also Bcl-xL Mcl-1 high affinities. Compound potently inhibits cell growth in PC-3 prostate cancer cells an IC50 200 effectively induces apoptosis dose-dependent manner.
XIAP is a central apoptosis regulator that inhibits by binding to and inhibiting the effectors caspase-3/-7 an initiator caspase-9 through its BIR2 BIR3 domains, respectively. Smac protein in dimeric form effectively antagonizes concurrently targeting both domains. We report design, synthesis, characterization of nonpeptide, cell-permeable, bivalent small-molecule (SM-164) which mimics for XIAP. Our study shows SM-164 binds containing BIR domains with IC50 value 1.39 nM, being 300 7000 times...
Histone post-translational modifications regulate chromatin structure and function largely through interactions with effector proteins that often contain multiple histone-binding domains. While significant progress has been made characterizing individual domains, the role of paired domains how they in a combinatorial fashion within are poorly defined. Here we show linked tandem Tudor plant homeodomain (PHD) UHRF1 (ubiquitin-like PHD RING finger domain-containing protein 1) operates as...
Indolicidin is a host defense tridecapeptide that inhibits the catalytic activity of HIV-1 integrase in vitro. Here we have elucidated its mechanism inhibition. Using crosslinking and mass spectrometric footprinting approaches, found indolicidin interferes with formation integrase-DNA complex by directly binding DNA. Further characterization revealed peptide forms covalent links abasic sites. crosslinks single- or double-stranded DNAs various positions viral cDNA comparable efficiency....
To investigate possible genotype-phenotype correlations and to evaluate the natural history of patients with Charcot-Marie-Tooth disease type 1X (CMT1X).CMT1X is caused by over 260 distinct mutations in gap junction beta 1 (GJB1) gene, located on X chromosome, which encodes protein connexin 32 (Cx32). The CMT1X poorly understood, it remains unknown whether particular cause more severe neuropathies through abnormal gain-of-function mechanisms.We evaluated 73 male CMT1X, who each have 28...
The epigenetic inheritance of DNA methylation requires UHRF1, a histone- and DNA-binding RING E3 ubiquitin ligase that recruits DNMT1 to sites newly replicated through ubiquitylation histone H3. UHRF1 binds with selectivity towards hemi-methylated CpGs (HeDNA); however, the contribution HeDNA sensing function remains elusive. Here, we reveal interaction is required for but dispensable chromatin interaction, which governed by reciprocal positive cooperativity between domains. recognition...
Elucidation of interactions involving DNA and histone post-translational-modifications (PTMs) is essential for providing insights into complex biological functions. Reader assemblies connected by flexible linkages facilitate avidity increase affinity; however, little known about the contribution to recognition process multiple PTMs because rigidity in absence conformational flexibility. Here, we resolve crystal structure triple reader module (PHD-BRD-PWWP) ZMYND8, which forms a stable unit...
Abstract Acetylation of histone H3K23 has emerged as an essential posttranslational modification associated with cancer and learning memory impairment, yet our understanding this epigenetic mark remains insufficient. Here, we identify the native MORF complex a H3K23-specific acetyltransferase elucidate its mechanism action. The function catalytic subunit is positively regulated by DPF domain (MORF ). crystal structure in crotonylated H3K14 peptide provides mechanistic insight into...
Abstract Background Plant homeodomain (PHD) fingers are central “readers” of histone post-translational modifications (PTMs) with > 100 PHD finger-containing proteins encoded by the human genome. Many PHDs studied to date bind unmodified or methylated states H3 lysine 4 (H3K4). Additionally, many these domains, and they contained in, have crucial roles in regulation gene expression cancer development. Despite this, majority gone uncharacterized; thus, our understanding how domains...
In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The latter state is expected to impact N-termini availability the epigenetic machinery. Notably, H3 tail acetylation (e.g. K9ac, K14ac, K18ac) linked increased H3K4me3 engagement by BPTF PHD finger, but it unknown if this mechanism has a broader extension. Here, we show that promotes nucleosomal accessibility other H3K4 methyl readers, importantly, extends writers,...
A successful structure-based design and synthesis of a class highly potent conformationally constrained Smac mimetics is described. The most compound has Ki value 25 nM binding to the XIAP BIR3 protein 23 times more than natural peptides. These can serve as powerful chemical pharmacological tools further elucidate role its cellular partners in apoptosis regulation may be developed new anti-cancer drugs.
A successful structure-based design of conformationally constrained second mitochondria-derived activator caspase (Smac) mimetics that target the XIAP/caspase-9 interaction site is described. The most potent Smac mimetic 12d has a Ki 350 nM for binding to XIAP BIR3 domain protein. found be effective in enhancing apoptosis induced by cisplatin PC-3 human prostate cancer cells.
To determine the rate of disease progression in Charcot-Marie-Tooth type 1A (CMT1A).CMT1A is most common inherited peripheral neuropathy, affecting approximately 1:5,000 people irrespective ethnic background or gender. There no cure for CMT1A. Clinical trials are being initiated that use CMT Neuropathy Score (CMTNS), a composite score based on patient symptoms, signs, and neurophysiologic abnormalities, as primary outcome variable. The sensitivity CMTNS any other to change over time, measure...