A5089853419- Cancer-related Molecular Pathways
- Mercury impact and mitigation studies
- Chemical Synthesis and Analysis
- Ubiquitin and proteasome pathways
- Crystallography and molecular interactions
- Monoclonal and Polyclonal Antibodies Research
- Protein Structure and Dynamics
- Enzyme Structure and Function
- X-ray Diffraction in Crystallography
- RNA and protein synthesis mechanisms
- Crystallization and Solubility Studies
- Heme Oxygenase-1 and Carbon Monoxide
- RNA Research and Splicing
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- Heavy Metal Exposure and Toxicity
- Peptidase Inhibition and Analysis
- Lipoproteins and Cardiovascular Health
- RNA modifications and cancer
- Autophagy in Disease and Therapy
- Biochemical and Structural Characterization
- Radiopharmaceutical Chemistry and Applications
- Chronic Lymphocytic Leukemia Research
- Glycosylation and Glycoproteins Research
- Genomics and Chromatin Dynamics
La Roche College
2004-2016
Université de Montréal
2004-2011
University of Georgia
2004-2009
National Institutes of Health
2008
University of Campania "Luigi Vanvitelli"
2005
University of California, Berkeley
2005
University of California, Irvine
2005
University of Naples Federico II
1999-2004
Institute of Biostructure and Bioimaging
2004
Institute of Molecular Biotechnology
2004
Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes p53-MDM2 binding inhibitors have developed. However, these compounds do not inhibit the p53-MDMX interaction, their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block with both MDM2 MDMX inhibitor-driven homo- and/or heterodimerization proteins....
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...
USP7 is a deubiquitinase implicated in destabilizing the tumor suppressor p53, and for this reason it has gained increasing attention as potential oncology target small molecule inhibitors. Herein we describe biophysical, biochemical, computational approaches that led to identification of 4-(2-aminopyridin-3-yl)phenol compounds described by Kategaya (Nature 2017, 550, 534–538) specific inhibitors USP7. Fragment based lead discovery (FBLD) NMR combined with virtual screening re-mining...
Erythroid Krüppel-like factor (EKLF) plays an important role in erythroid development by stimulating β-globin gene expression. We have examined the details which minimal transactivation domain (TAD) of EKLF (EKLFTAD) interacts with several transcriptional regulatory factors. report that EKLFTAD displays homology to p53TAD and, like p53TAD, can be divided into two functional subdomains (EKLFTAD1 and EKLFTAD2). Based on sequence analysis, we found EKLFTAD2 is conserved KLF2, KLF4, KLF5, KLF15....
Bacteria resistant to methylmercury utilize two enzymes (MerA and MerB) degrade the less toxic elemental mercury. The crucial step is cleavage of carbon-mercury bond by organomercurial lyase (MerB). In this study, we determined high resolution crystal structures MerB in both free (1.76-A resolution) mercury-bound (1.64-A states. structure very similar NMR structure, but important differences are observed when comparing structures. an amino-terminal alpha-helix that not present makes contact...
The Herpes Simplex Virion Protein 16 (VP16) activates transcription through a series of protein/protein interactions involving its highly acidic transactivation domain (TAD). TAD VP16 (VP16TAD) has been shown to interact with several partner proteins both in vitro and vivo, many these partners also bind the mammalian tumor suppressor protein p53. For example, TADs p53 (p53TAD) directly p62/Tfb1 (human/yeast) subunit TFIIH, this interaction correlates their ability activate initiation...
Bacteria isolated from organic mercury-contaminated sites have developed a system of two enzymes that allows them to efficiently convert both ionic and mercury compounds the less toxic elemental mercury. Both are encoded on mer operon require sulfhydryl-bound substrates. The first enzyme is an organomercurial lyase (MerB), second mercuric ion reductase (MerA). MerB catalyzes protonolysis carbon-mercury bond, resulting in formation reduced carbon compound inorganic Of several...
The general transcription factor IIH is recruited to the preinitiation complex through an interaction between its p62/Tfb1 subunit and α-subunit of IIE (TFIIEα). We have determined that acidic carboxyl terminus TFIIEα (TFIIEα 336–439 ) directly binds amino-terminal PH domain with nanomolar affinity. NMR mapping mutagenesis studies demonstrate binding site on identical for second transactivation p53 (p53 TAD2). In addition, we capable competing a common diphosphorylated form (pS46/pT55) TAD2...
Several peptide hormones are initially synthesized as inactive precursors. It is only on entry of these prohormones and their processing proteases into dense core secretory granules (DCSGs) that the precursors cleaved to generate active forms. Prohormone convertase (PC)1/3 a protease targeted DCSGs. The signal for targeting PC1/3 DCSGs resides in its carboxy-terminal tail (PC1/3 617–753 ), where 3 regions 617–625 , 665–682 711–753 ) known aid sorting membrane association. In this article, we...
TARGETING PPIS: A novel strategy for designing libraries targeting protein-protein interfaces enabled us to identify diverse chemical entry points interact with therapeutic targets which conventional screening delivered no or only few hit structures. The concept was experimentally validated by early evaluation in biochemical screens and ADMET profiling.
General transcription factor IIH (TFIIH) is recruited to the preinitiation complex (PIC) through direct interactions between its p62 (Tfb1) subunit and carboxyl-terminal domain of TFIIEalpha. TFIIH has also been shown interact with a number transcriptional activator proteins same subunit. We have determined NMR solution structure amino-terminal from Tfb1 yeast (Tfb1(1-115)). Like corresponding human protein, Tfb1(1-115) contains PH fold despite low level sequence identity two functionally...
Nuclear magnetic resonance (NMR) data from NOESY (nuclear Overhauser enhancement spectroscopy) and ROESY (rotating frame experiments can easily be combined with distance geometry (DG) based conformer generators by modifying the molecular bounds matrix. In this work, we extend modern DG generator ETKDG, which has been shown to reproduce experimental crystal structures small molecules large macrocycles well, include NOE-derived interproton distances. noeETKDG, experimentally derived distances...
Zinc finger domains of the classical type represent most abundant DNA binding in eukaryotic transcription factors. Plant proteins contain from one to four zinc domains, which are characterized by high conservation sequence QALGGH, shown be critical for DNA-binding activity. The Arabidopsis thaliana SUPERMAN protein, contains a single QALGGH finger, is necessary proper spatial development reproductive floral tissues and has been specifically bind DNA. Here, we report synthesis UV NMR...
ABSTRACT The papillomavirus E1 helicase, with the help of E2, assembles at viral origin into a double hexamer that orchestrates replication genome. N-terminal region (NTR) is essential for DNA in vivo but dispensable vitro , suggesting it has regulatory function. By deletion analysis, we identified conserved NTR needed efficient DNA. This predicted to form an amphipathic α-helix (AH) and shows sequence similarity portions p53 herpes simplex virus (HSV) VP16 transactivation domains known as...
Mercury resistant bacteria have developed a system of two enzymes (MerA and MerB), which allows them to efficiently detoxify both ionic organomercurial compounds. The lyase (MerB) catalyzes the protonolysis carbon−mercury bond resulting in formation mercury reduced hydrocarbon. [Hg(II)] is subsequently less reactive elemental [Hg(0)] by specific mercuric reductase (MerA). To better understand MerB's unique enzymatic activity, we used nuclear magnetic resonance (NMR) spectroscopy determine...
Doublecortin is a microtubule-associated protein produced during neurogenesis. The stabilizes microtubules and stimulates their polymerization, which allows migration of immature neurons to designated location in the brain. Mutations gene that impair doublecortin function cause severe brain formation disorders are located on tandem repeat two domains. molecular mechanism action only incompletely understood. Anti-doublecortin antibodies, such as rabbit polyclonal Abcam 18732, widely used...
Recycling of RNA polymerase II (RNAPII) requires dephosphorylation the C-terminal domain (CTD) largest subunit polymerase. FCP1 enables recycling RNAPII via its CTD-specific phosphatase activity, which is stimulated by RAP74 general transcription factor TFIIF. Both central (centFCP1) and (cterFCP1) domains interact independently specifically with (cterRAP74), suggesting that these interactions mediate stimulatory effect TFIIF on CTD activity FCP1. Phosphorylation casein kinase 2 residues in...
No general strategy for thermostability has been yet established, because the extra stability of thermophiles appears to be sum different cumulative stabilizing interactions. In addition, increase conformational rigidity observed in many thermophilic proteins, which some cases disappears when mesophilic and proteins are compared at their respective physiological temperatures, suggests that evolutionary adaptation tends maintain corresponding states with respect flexibility. this study, we...