A5091330499- DNA and Nucleic Acid Chemistry
- RNA and protein synthesis mechanisms
- Advanced biosensing and bioanalysis techniques
- DNA Repair Mechanisms
- RNA Interference and Gene Delivery
- RNA modifications and cancer
- Photosynthetic Processes and Mechanisms
- Bacteriophages and microbial interactions
- HIV/AIDS drug development and treatment
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Cancer therapeutics and mechanisms
- Enzyme Structure and Function
- Circadian rhythm and melatonin
- Light effects on plants
- Bacterial Genetics and Biotechnology
- Carcinogens and Genotoxicity Assessment
- Analytical Chemistry and Chromatography
- Chemical Synthesis and Analysis
- Photoreceptor and optogenetics research
- Carbohydrate Chemistry and Synthesis
- CRISPR and Genetic Engineering
- RNA Research and Splicing
- Fluorine in Organic Chemistry
- Epigenetics and DNA Methylation
Vanderbilt University
2016-2025
Vanderbilt-Ingram Cancer Center
2021-2025
Vanderbilt Health
2025
Indiana University School of Medicine
2014-2019
Nashville Oncology Associates
2013-2019
Northwestern University
1996-2018
Massachusetts Institute of Technology
1990-2018
Institute of Chemical Biology and Fundamental Medicine
2016
Joint Center for Structural Genomics
2016
Milbank Memorial Fund
2010-2012
The ability of aromatic rings to act as acceptors in hydrogen bonds has been demonstrated extensively both by experimental and theoretical means. Countless examples D−H···π (H···π, D = O, N, C) interactions have found the three-dimensional structures proteins. Much less is known with regard occurrence other possible noncovalent aromatics macromolecular structures, those a geometry that points oxygen lone pairs into face π system. There growing interest such lp···π recent years, but binding...
The conjugation of the sense strands small interfering RNA (siRNA) to tri-N-acetylgalactosamine (GalNAc), ligand for a hepatocyte-specific receptor, enables delivery multiple clinically approved therapeutic agents that act through interference pathway. Here, we report systematic evaluation siRNAs with 3′ termini antisense conjugated GalNAc first time. These designs retained same receptor affinity, in vitro and vivo activities, as well level loading into RNA-induced silencing complex...
While B-DNA, the most common DNA conformation, displays rather regular twist angles and base stacking between successive pairs, left-handed Z-DNA is characterized by alternation of two different dinucleotide conformations with either a large small slide or adjacent pairs. This results in poor within latter repeat that apparent contradiction to rigidity conformational stability at high ionic strength. However, d(CpG) steps cytidine deoxyribose situated such its O4' sits directly over...
The crystal structure of the RNA duplex [r(CCCCGGGG)]2 has been refined to 1.46 Å resolution with room temperature synchrotron diffraction data. This represents highest reported date for an all-RNA oligonucleotide and is well beyond best ever achieved A-form DNA duplex. analysis ordered hydration around octamer reveals conserved regular arrangements water molecules in both grooves. In major groove, all located first shell can be fitted into a pattern that repeated through eight base pairs,...
Various chemical modifications are currently being evaluated for improving the efficacy of short interfering RNA (siRNA) duplexes as antisense agents gene silencing in vivo . Among 2′-ribose assessed to date, 2′deoxy-2′-fluoro-RNA (2′-F-RNA) has unique properties interference (RNAi) applications. Thus, 2′-F-modified nucleotides well tolerated guide (antisense) and passenger (sense) siRNA strands corresponding lack immunostimulatory effects, enhance nuclease resistance display improved vitro...
With little or no negative impact on the activity of small interfering RNAs (siRNAs), regardless number modifications positions within strand, 2′-deoxy-2′-fluoro (2′-F) modification is unique. Furthermore, 2′-F-modified siRNA (see crystal structure) was thermodynamically more stable and nuclease-resistant than parent siRNA, produced immunostimulatory response. Detailed facts importance to specialist readers are published as "Supporting Information". Such documents peer-reviewed, but not...
Efforts to chemically modify nucleic acids got underway merely a decade after the discovery of DNA double helix and initially targeted nucleosides nucleotides. The origins three analogues that remain staples modification strategies figure prominently in FDA-approved acid therapeutics can be traced 1960s: 2'-deoxy-2'-fluoro-RNA (2'-F RNA), 2'- O-methyl-RNA (2'- OMe phosphorothioates (PS-DNA/RNA). Progress nucleoside phosphoramidite-based solid phase oligonucleotide synthesis has gone hand...
RNA aptamers are synthetic oligonucleotide-based affinity molecules that utilize unique three-dimensional structures for their and specificity to a target such as protein. They hold the promise of numerous advantages over biologically produced antibodies; however, binding often insufficient successful implementation in diagnostic assays or therapeutic agents. Strong is important improve downstream applications. We report here use phosphorodithioate (PS2) substitution on single nucleotide...
Abstract Preclinical mechanistic studies have pointed towards RNA interference-mediated off-target effects as a major driver of hepatotoxicity for GalNAc–siRNA conjugates. Here, we demonstrate that single glycol nucleic acid or 2′–5′-RNA modification can substantially reduce small interfering (siRNA) seed-mediated binding to transcripts while maintaining on-target activity. In siRNAs with established driven by effects, these novel designs seed-pairing destabilization, termed enhanced...
Glycol nucleic acid (GNA) is an acyclic analog connected via phosphodiester bonds. Crystal structures of RNA-GNA chimeric duplexes indicated that nucleotides the right-handed (S)-GNA were better accommodated in RNA duplex than left-handed (R)-isomers. GNA adopt a rotated nucleobase orientation within all contexts, pairing with complementary reverse Watson-Crick mode, which explains inabilities C and G to form strong base pairs nucleotides. Transposition hydrogen bond donor acceptor using...
The minor groove hydration spine is a key feature of the crystal structure B-DNA dodecamer duplex (d(CGCGAATTCGCG)) 2. At floor groove, water molecules bridge bases from opposite strands by hydrogen bonding to N3 and O2 atoms adenine thymine, respectively. However, interpretation that series electron density peaks lining represents indeed molecules, while generally agreed upon, remains an assumption. limited resolutions structures have thus far made it impossible reliably distinguish between...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTThe Dickerson-Drew B-DNA Dodecamer Revisited at Atomic ResolutionValentina Tereshko, George Minasov, and Martin EgliView Author Information Department of Molecular Pharmacology Biological Chemistry The Drug Discovery Program Northwestern University Medical School Chicago, Illinois 60611-3008 Cite this: J. Am. Chem. Soc. 1999, 121, 2, 470–471Publication Date (Web):December 23, 1998Publication History Received15 September 1998Published online23...
DNA fragments with stretches of cytosine residues can fold into four-stranded structures in which two parallel duplexes, held together by hemiprotonated cytosine.cytosine+ (C.C+) base pairs, intercalate each other opposite polarity. The structural details this intercalated quadruplex have been assessed solution NMR and single crystal x-ray diffraction studies cytosine-rich sequences, including those present metazoan telomeres. A conserved feature these is the absence stabilizing stacking...
1,N(2)-Etheno(epsilon)guanine is a mutagenic DNA lesion derived from lipid oxidation products and also some chemical carcinogens. Gel electrophoretic analysis of the primer extension by Sulfolobus solfataricus P2 polymerase IV (Dpo4) indicated preferential incorporation A opposite 3'-(1,N(2)-epsilon-G)TACT-5', among four dNTPs tested individually. With template 3'-(1,N(2)-epsilon-G)CACT-5', both G were incorporated. When was done in presence mixture all dNTPs, high pressure liquid...
In cyanobacteria, KaiC is an essential hexameric clock protein that forms the core of a circadian complex. can be phosphorylated, and ratio phospho-KaiC to non-phospho-KaiC correlated with period. Structural analyses crystals identify three potential phosphorylation sites within 10-A radius ATP binding regions are at T432, S431, T426 residues in KaiCII domains. When these mutated by alanine substitution singly or combination, altered, rhythmicity abolished. These substitutions do not prevent...