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.
College of Pharmacy, The University of Arizona, 1703 East Mabel, Tucson, Arizona 85721, USA.
Evonne M
EM
Rezler
Jeyaprakashnarayanan
J
Seenisamy
Sridevi
S
Bashyam
Mu-Yong
MY
Kim
Elizabeth
E
White
W David
WD
Wilson
Laurence H
LH
Hurley
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