Structure of the Hybrid-2 type intramolecular human telomeric G-quadruplex in K+ solution: insights into structure polymorphism of the human telomeric sequence.
Formation of the G-quadruplex in the human telomeric sequence can inhibit the activity of telomerase, thus the intramolecular telomeric G-quadruplexes have been considered as an attractive anticancer target. Information of intramolecular telomeric G-quadruplex structures formed under physiological conditions is important for structure-based drug design. Here, we report the first structure of the major intramolecular G-quadruplex formed in a native, non-modified human telomeric sequence in K(+) solution. This is a hybrid-type mixed parallel/antiparallel-G-stranded G-quadruplex, one end of which is covered by a novel T:A:T triple capping structure. This structure (Hybrid-2) and the previously reported Hybrid-1 structure differ in their loop arrangements, strand orientations and capping structures. The distinct capping structures appear to be crucial for the favored formation of the specific hybrid-type intramolecular telomeric G-quadruplexes, and may provide specific binding sites for drug targeting. Our study also shows that while the hybrid-type G-quadruplexes appear to be the major conformations in K(+) solution, human telomeric sequences are always in equilibrium between Hybrid-1 and Hybrid-2 structures, which is largely determined by the 3'-flanking sequence. Furthermore, both hybrid-type G-quadruplexes suggest a straightforward means for multimer formation with effective packing in the human telomeric sequence and provide important implications for drug targeting of G-quadruplexes in human telomeres.
Dai
Jixun
J
College of Pharmacy, The University of Arizona, 1703 E. Mabel St, Tucson, AZ 85721, USA.
Carver
Megan
M
Punchihewa
Chandanamali
C
Jones
Roger A
RA
Yang
Danzhou
D
D001483:Base Sequence; D004247:DNA / Q000737:chemistry*; D004252:DNA Mutational Analysis; D054856:G-Quadruplexes; D006147:Guanine / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation; D011188:Potassium / Q000737:chemistry; D011522:Protons; D012996:Solutions; D016615:Telomere / Q000737:chemistry*
D011522:Protons; D012996:Solutions; D006147:Guanine; D004247:DNA; D011188:Potassium