The goal of my PhD thesis project was to obtain information about the biophysical characteristics of a potentially biologically significant higher-order DNA structural motif. We have been interested in structures of DNA quadruplexes whose core architecture is based on guanine quartets (G-quartets). It has been suggested that G-quartet structures may form at the natural eukaryotic chromosome ends (telomeres) and contribute to protein binding, regulation, or resistance to degradation. Telomeres are usually composed of simple tandem repeats of guanine-rich sequences associated with telomeric binding proteins. Telomeric sequences are typically found to be highly conserved across phylogenetically diverse organisms. More recently, however, many budding yeast telomeres have been shown to have more divergent sequences both in length and in base composition. Oligonucleotides having one to two repeats of the yeast telomeric sequences are usually less stable thermodynamically compared to those with more conserved sequences, such as ones from ciliate protozoa. My thesis project involved the characterization of several quadruplex-forming guanine-rich oligonucleotides from budding yeast telomeric and related sequences. Solution nuclear magnetic resonance (NMR) and other spectroscopic methods were used to understand their physical chemical features, the factors contributing to the stability of the complexes, and to determine high resolution solution structures of those oligonucleotides. The recent improvement of our NMR spectrum analysis tool, Sparky, has been very useful for our structural determination process. The capability of the program to visualize structural models and inter-proton distances using MidasPlus within Sparky accelerated tis process enormously. The incorporation of graphical tools to the structural determination process, spectrum analysis (Sparky), distance calculation (MARDIGRAS), structure elucidation (Amber, X-PLOR) was exciting and it has already helped the iterative nature of this process.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR001081-21
Application #
6280309
Study Section
Project Start
1998-07-01
Project End
1999-06-30
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
21
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Kozak, John J; Gray, Harry B; Garza-López, Roberto A (2018) Relaxation of structural constraints during Amicyanin unfolding. J Inorg Biochem 179:135-145
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Chu, Shidong; Zhou, Guangyan; Gochin, Miriam (2017) Evaluation of ligand-based NMR screening methods to characterize small molecule binding to HIV-1 glycoprotein-41. Org Biomol Chem 15:5210-5219
Portioli, Corinne; Bovi, Michele; Benati, Donatella et al. (2017) Novel functionalization strategies of polymeric nanoparticles as carriers for brain medications. J Biomed Mater Res A 105:847-858
Alamo, Lorenzo; Koubassova, Natalia; Pinto, Antonio et al. (2017) Lessons from a tarantula: new insights into muscle thick filament and myosin interacting-heads motif structure and function. Biophys Rev 9:461-480
Nguyen, Hai Dang; Yadav, Tribhuwan; Giri, Sumanprava et al. (2017) Functions of Replication Protein A as a Sensor of R Loops and a Regulator of RNaseH1. Mol Cell 65:832-847.e4
Sofiyev, Vladimir; Kaur, Hardeep; Snyder, Beth A et al. (2017) Enhanced potency of bivalent small molecule gp41 inhibitors. Bioorg Med Chem 25:408-420
Kozak, John J; Gray, Harry B; Garza-López, Roberto A (2016) Cytochrome unfolding pathways from computational analysis of crystal structures. J Inorg Biochem 155:44-55
Amlong, Corey A; Perkins, Mark G; Houle, Timothy T et al. (2016) Contrasting Effects of the ?-Aminobutyric Acid Type A Receptor ?3 Subunit N265M Mutation on Loss of Righting Reflexes Induced by Etomidate and the Novel Anesthetic Barbiturate R-mTFD-MPAB. Anesth Analg 123:1241-1246

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