Zhang, Yipeng; Lan, Wenxian; Wang, Chunxi; Xue, Hongjuan; Cao, Chunyang

CHINESE JOURNAL OF CHEMISTRY

2022, 40, 1001-604X

Zhang, Yipeng; Lan, Wenxian; Wang, Chunxi; Xue, Hongjuan; Cao, Chunyang

Comprehensive Summary Vascular endothelial growth factor (VEGF) regulates tumor angiogenesis, which is active on the endothelium via VEGF receptor 2 (VEGFR-2). The proximal promoter region of VEGFR-2 (termed as VEGFR-2 DNA) is guanine-rich, forming G-quadruplex (G4) structures. Here, we demonstrate that VEGFR-2 DNA consists of one symmetrically dimeric 14-mer G4-DNA and one 12-mer sequence-palindromic dsDNA. This G4-DNA adopts an unprecedented folding with five stacked tetrads linked by four broken strands. Its 5'-end part contains an A-tetrad A(1)center dot A(4)center dot A(1')center dot A(4') and one G-tetrad G(3)center dot G(5)center dot G(3')center dot G(5') with two V-shaped loops and two one-nt edge-type loops. Its 3'-end part includes three G-tetrads G(10)center dot G(6)center dot G(10')center dot G(6'), G(11)center dot G(7)center dot G(11')center dot G(7') (central) and G(12)center dot G(8)center dot G(12')center dot G(8') spanned by two double-chain-reversal one-nt (C-9 or C-9') loops. Bases G(13) and G(13') stack with G-tetrad G(12)center dot G(8)center dot G(12')center dot G(8'). These characteristics make this G4-DNA more stable than reported VEGFR-17T G4 structure. The dsDNA connects with G4-DNA without any interactions, generating a linear assembly with G4-DNA structural bulges. These studies uncover new structural features of VEGFR-2 DNA as a potential drug target by inhibiting VEGFR-2 expression, thereby tumor angiogenesis.