This competing renewal outlines a research program that applies NMR and x-ray crystallographic approaches to the structures, transitions and recognition of multistranded DNA architectures. New motifs identified during the last renewal ranged from triads, to mixed tetrads, pentads and hexads, as well as double chain reversal loops and V-shaped scaffolds. New motifs currently under investigation include G*G*G triple platforms, mixed G*A*G*A tetrads, duplex-quadruplex junctions and mini triad DNA. A new project will address the structures and interconversions between competing quadruplex folds adopted by a guanine repeat-containing oncogenic c-myc promotor element. We have determined the structure of a novel dimeric interdigitated quadruplex containing double chain reversal loops, which targets the core domain of HIV-1 integrase with nanomolar affinity. Studies of complex formation are currently underway and should elucidate the principles by which this very stable scaffold projects unique bases for potential targeting of the catalytic pocket on the integrase. The guanine plus adenine rich triplet repeats (GAA)n and (GGA)n appear to adopt parallel-stranded duplexes stabilized by reverse G*G and A*A non-canonical pairs, which adopt sequence-dependent distinct pairing alignments. We are currently experimentally testing a parallel-stranded DNA duplex model for self-pairing by the Friedrichs ataxia triplet repeat disease all purine (GAA)n sequence. We are well positioned to monitor both structural and energetics aspects of conformational interconversions between quadruplex folds adopted by two repeat human telomere TTAGGG and Tetrahymena telomere TTGGGG sequences, and their modulation by quadruplex-binding ligands. Parallel structure-energetics studies will be undertaken on two repeat centromeric sequences.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034504-20
Application #
6830808
Study Section
Physical Biochemistry Study Section (PB)
Program Officer
Lewis, Catherine D
Project Start
1984-12-01
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
20
Fiscal Year
2005
Total Cost
$379,125
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Kuryavyi, Vitaly; Cahoon, Laty A; Seifert, H Steven et al. (2012) RecA-binding pilE G4 sequence essential for pilin antigenic variation forms monomeric and 5' end-stacked dimeric parallel G-quadruplexes. Structure 20:2090-102
Ren, Aiming; Rajashankar, Kanagalaghatta R; Patel, Dinshaw J (2012) Fluoride ion encapsulation by Mg2+ ions and phosphates in a fluoride riboswitch. Nature 486:85-9
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Pikovskaya, Olga; Polonskaia, Anna; Patel, Dinshaw J et al. (2011) Structural principles of nucleoside selectivity in a 2'-deoxyguanosine riboswitch. Nat Chem Biol 7:748-55
Kuryavyi, Vitaly; Patel, Dinshaw J (2010) Solution structure of a unique G-quadruplex scaffold adopted by a guanosine-rich human intronic sequence. Structure 18:73-82
Pikovskaya, Olga; Serganov, Artem A; Polonskaia, Ann et al. (2009) Preparation and crystallization of riboswitch-ligand complexes. Methods Mol Biol 540:115-28
Serganov, Alexander; Patel, Dinshaw J (2009) Amino acid recognition and gene regulation by riboswitches. Biochim Biophys Acta 1789:592-611
Westhof, Eric; Patel, Dinshaw J (2009) Nucleic acids: how high resolution structural biology help us to understand Darwinian evolution. Curr Opin Struct Biol 19:235-8
Lim, Kah Wai; Amrane, Samir; Bouaziz, Serge et al. (2009) Structure of the human telomere in K+ solution: a stable basket-type G-quadruplex with only two G-tetrad layers. J Am Chem Soc 131:4301-9

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