A5036421734- Acute Myeloid Leukemia Research
- Chronic Myeloid Leukemia Treatments
- Chronic Lymphocytic Leukemia Research
- DNA Repair Mechanisms
- DNA and Nucleic Acid Chemistry
- Supramolecular Chemistry and Complexes
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Enzyme Structure and Function
- RNA modifications and cancer
- Bacterial Genetics and Biotechnology
- Crystallization and Solubility Studies
- Viral Infections and Immunology Research
- X-ray Diffraction in Crystallography
- Chemical Synthesis and Analysis
- Metal complexes synthesis and properties
- Molecular Sensors and Ion Detection
- HIV Research and Treatment
- biodegradable polymer synthesis and properties
- Viral gastroenteritis research and epidemiology
- Crystallography and molecular interactions
- ATP Synthase and ATPases Research
- Molecular Junctions and Nanostructures
- RNA Interference and Gene Delivery
- Malaria Research and Control
University of Arkansas for Medical Sciences
2021-2025
Winthrop Rockefeller Foundation
2024
St. Jude Children's Research Hospital
2013-2022
University of Tennessee Health Science Center
2013-2015
Cold Spring Harbor Laboratory
2000-2014
W. M. Keck Foundation
2014
University of Tennessee at Knoxville
2013
Stanford University
1995-1998
The DNA translocation activity of the minichromosome maintenance (MCM) complex powers strand separation replication forks eukaryotes and archaea. Here we illustrate an atomic level mechanism for this with a crystal structure archaeal MCM hexamer bound to single-stranded nucleotide cofactors. Sequence conservation indicates rotary is fully possible all definitively demonstrates ring orients during N-terminal domain leading, indicating that could also provide physical basis initiation where...
The chirality alone of a conformationally restricted, bifunctional ligand (L) is the basis for self-recognition process schematically represented below. A racemic mixture these ligands reacts with Cu+ ions quantitatively to generate [(CuL)2]2+ homochiral complex (represented by cubes), where each contains identical configurations.
Abstract Purpose: To evaluate the clinical activity of sequential therapy with sorafenib and sunitinib in FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myelogenous leukemia (AML) monitor emergence secondary FLT3 domain (TKD) mutations during treatment. Experimental Design: Six children relapsed/refractory AML were treated combination clofarabine cytarabine, followed by single-agent if not a candidate for transplantation. Sunitinib was initiated after...
The DEAD-box RNA helicase DDX3X is frequently mutated in pediatric medulloblastoma. We dissect how these mutants affect function with structural, biochemical, and genetic experiments. identify an N-terminal extension (“ATP-binding loop”, ABL) that critical for the stimulation of ATP hydrolysis by RNA. present crystal structures suggesting ABL interacts dynamically confirming interaction occurs solution NMR chemical shift perturbation isothermal titration calorimetry. helicases require...
The ring-shaped MCM helicase is essential to all phases of DNA replication. complex loads at replication origins as an inactive double-hexamer encircling duplex DNA. Helicase activation converts this species two active single hexamers that encircle single-stranded (ssDNA). molecular details interactions during these events are unknown. We determined the crystal structure Pyrococcus furiosus N-terminal domain hexamer bound ssDNA and define a conserved MCM-ssDNA binding motif (MSSB)....
<em>Angewandte Chemie International Edition</em> is one of the prime chemistry journals in world, publishing research articles, highlights, communications and reviews across all areas chemistry.
Significance Precise replication of the genome is essential for maintaining integrity genetic information in all forms life. A key step this process unwinding DNA double helix, a subject intensive research and debate. We took multifaceted approach to study fundamental mechanisms helicase function, using E1 from papillomavirus. Our findings reveal that employs strand exclusion mechanism unwind with N-terminal side leading at fork. Intriguingly, by modulated origin-recognition domain,...
In a previous Research article (<xref ref-type="bibr" rid="bib25">Froelich et al., 2014</xref>), we suggested an MCM helicase activation mechanism, but were limited in discussing the ATPase domain because it was absent from crystal structure. Here present structure of nearly full-length hexamer that is helicase-active and thus has all features essential for unwinding DNA. The chimera Sulfolobus solfataricus N-terminal Pyrococcus furiosus domain. We discuss three major findings:...
DNA replication is tightly regulated to ensure genomic stability and prevent several diseases, including cancers. Eukaryotes archaea partly achieve this regulation by strictly controlling the activation of hexameric minichromosome maintenance (MCM) helicase rings that unwind during its replication. In eukaryotes, MCM critically relies on sequential recruitment essential factors Cdc45 a tetrameric GINS complex at onset S-phase generate larger CMG complex. We present crystal structure from...
The structurally diverse group of bis(catecholamide) bacterial siderophores is intriguing because these molecules lack a sufficient number ligating atoms to fully complex one iron atom as 1:1 complex. Any containing fully-complexed ligated exclusively by inherently requires multiple ligands bind metals, demonstrating biological example metal-assisted self-assembly. Two new ferric coordination modes ligand are and spectroscopically characterized 2:3 dinuclear triple helix 2:2 bis(μ-hydroxo)...
Ausschließlich auf der Chiralität bifunktionellen, konformativ eingeschränkten Liganden L beruht deren unten schematisch dargestellte Selbsterkennung. Ein Racemat dieser reagiert mit CuI quantitativ ebenfalls zu einem eines homoleptischen [{Cu(L)}2]2+-Komplexes (dargestellt durch Würfel), wobei aber jeder Komplex gleichartig konfigurierte enthält.
Abstract The enteroviral 2C protein is a therapeutic target, but the absence of mechanistic framework for this enzyme limits our understanding inhibitor mechanisms. Here, we use poliovirus and derivative thereof to elucidate first biochemical mechanism confirm applicability other members enterovirus genus. Our data are consistent with dimer forming in solution, binding RNA, which stimulates ATPase activity by increasing rate hydrolysis without impacting affinity ATP substantially. Both RNA...
Der chirale, zweizähnige Ligand (S,S)-1 reagiert mit Ga3+ stereospezifisch zu einem molekularen [Ga4(L)6]12−-Tetraeder, während ähnlichen Liganden [Ga2(L)3]6−-Komplexe entstehen. Die Spezifität bei der Komplexbildung ist bemerkenswert, denn Verwendung von rac-1 ordnen sich die selbstselektiv nach ihrer Chiralität und bilden ein Enantiomerenpaar homochiralen Komplexen.
The hexameric Minichromosome Maintenance (MCM) protein complex forms a ring that unwinds DNA at the replication fork in eukaryotes and archaea. Our recent crystal structure of an archaeal MCM N-terminal domain bound to single-stranded (ssDNA) revealed ssDNA associating across tight subunit interfaces but not loose interfaces, indicating DNA-binding is governed only by residues subunits (MCM ssDNA-binding motif, MSSB) also relative orientation subunits. We now extend these findings showing...