8IJC

NMR solution structure of the 1:1 complex of a platinum(II) ligand L1-transpt covalently bound to a G-quadruplex MYT1L

8IJC の概要

• エントリーDOI: 10.2210/pdb8ijc/pdb
• 分子名称: G-quadruplex DNA MYT1L, Pt(NH3)2(2-(pyridin-4-ylmethyl)benzo-[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone) (2 entities in total)
• 機能のキーワード: g-quadruplex dna, quadruplex-duplex hybrid, platinum complex, dna
• 由来する生物種: Homo sapiens
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 9803.36

構造登録者

Liu, L.-Y.,Mao, Z.-W. (登録日: 2023-02-27, 公開日: 2023-06-28, 最終更新日: 2024-05-15)

主引用文献

Liu, L.Y.,Ma, T.Z.,Zeng, Y.L.,Liu, W.,Zhang, H.,Mao, Z.W.
Organic-Platinum Hybrids for Covalent Binding of G-Quadruplexes: Structural Basis and Application to Cancer Immunotherapy.
Angew.Chem.Int.Ed.Engl., 62:e202305645-e202305645, 2023

PubMed Abstract: G-quadruplexes (G4s) have been revived as promising therapeutic targets with the development of immunotherapy, but the G4-mediated immune response remains unclear. We designed a novel class of G4-binding organic-platinum hybrids, L -cispt and L -transpt, with spatial matching for G4 binding and G4 DNA reactivity for binding site locking. The solution structure of L -transpt-MYT1L G4 demonstrated the effectiveness of the covalent binding and revealed the covalent binding-guided dynamic balance, accompanied by the destruction of the A5-T17 base pairs to achieve the covalent binding of the platinum unit to N7 of the G6 residue. Furthermore, L -cispt- and L -transpt-mediated genomic dysfunction could activate the retinoic acid-induced gene I (RIG-I) pathway and induce immunogenic cell death (ICD). The use of L -cispt/L -transpt-treated dying cells as therapeutic vaccines stimulated a robust immune response and effectively inhibited tumor growth in vivo. Our findings highlight the importance of the rational combination of specific spatial recognition and covalent locking in G4-trageting drug design and their potential in immunotherapy.

PubMed: 37464955
DOI: 10.1002/anie.202305645

実験手法

SOLUTION NMR