Telomestatin and diseleno sapphyrin bind selectively to two different forms of the human telomeric G-quadruplex structure.
The human telomeric sequence d[T(2)AG(3)](4) has been demonstrated to form different types of G-quadruplex structures, depending upon the incubation conditions. For example, in sodium (Na(+)), a basket-type G-quadruplex structure is formed. In this investigation, using circular dichroism (CD), biosensor-surface plasmon resonance (SPR), and a polymerase stop assay, we have examined how the addition of different G-quadruplex-binding ligands affects the conformation of the telomeric G-quadruplex found in solution. The results show that while telomestatin binds preferentially to the basket-type G-quadruplex structure with a 2:1 stoichiometry, 5,10,15,20-[tetra-(N-methyl-3-pyridyl)]-26-28-diselena sapphyrin chloride (Se2SAP) binds to a different form with a 1:1 stoichiometry in potassium (K(+)). CD studies suggest that Se2SAP binds to a hybrid G-quadruplex that has strong parallel and antiparallel characteristics, suggestive of a structure containing both propeller and lateral, or edgewise, loops. Telomestatin is unique in that it can induce the formation of the basket-type G-quadruplex from a random coil human telomeric oligonucleotide, even in the absence of added monovalent cations such as K(+) or Na(+). In contrast, in the presence of K(+), Se2SAP was found to convert the preformed basket G-quadruplex to the hybrid structure. The significance of these results is that the presence of different ligands can determine the type of telomeric G-quadruplex structures formed in solution. Thus, the biochemical and biological consequences of binding of ligands to G-quadruplex structures found in telomeres and promoter regions of certain important oncogenes go beyond mere stabilization of these structures.
Rezler
Evonne M
EM
College of Pharmacy, The University of Arizona, 1703 East Mabel, Tucson, Arizona 85721, USA.
Seenisamy
Jeyaprakashnarayanan
J
Bashyam
Sridevi
S
Kim
Mu-Yong
MY
White
Elizabeth
E
Wilson
W David
WD
Hurley
Laurence H
LH
D001665:Binding Sites; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D054856:G-Quadruplexes; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism; D015513:Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011166:Porphyrins / Q000737:chemistry / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D018036:Selenium Compounds / Q000737:chemistry / Q000378:metabolism*; D012964:Sodium / Q000494:pharmacology; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance; D016615:Telomere / Q000737:chemistry / Q000378:metabolism*
D008024:Ligands; D009841:Oligonucleotides; D015513:Oncogene Proteins; D010080:Oxazoles; D011166:Porphyrins; D018036:Selenium Compounds; C440448:sapphyrin; C431888:telomestatin; D004247:DNA; D012964:Sodium; D011188:Potassium