6KXZ

HUMAN PARALLEL STRANDED 7-MER G-QUADRUPLEX COMPLEXED WITH 2 EPIRUBICIN (EPI) MOLECULES

Summary for 6KXZ

• Entry DOI: 10.2210/pdb6kxz/pdb
• Descriptor: [TTAGGGT]4-EPI-Complex, 4'-EPIDOXORUBICIN (2 entities in total)
• Functional Keywords: g-quadruplex, epirubicin, epiadriamycin, dna
• Biological source: Homo sapiens
• Total number of polymer chains: 4
• Total formula weight: 9762.83

Authors

Barthwal, R.,Raje, S.,Pandav, K. (deposition date: 2019-09-15, release date: 2020-09-16, Last modification date: 2024-05-15)

Primary citation

Barthwal, R.,Raje, S.,Pandav, K.
Structural basis for stabilization of human telomeric G-quadruplex [d-(TTAGGGT)] 4 by anticancer drug epirubicin.
Bioorg.Med.Chem., 28:115761-115761, 2020

PubMed Abstract: Anthracycline anticancer drugs show multiple strategies of action on gene functioning by regulation of telomerase enzyme by apoptotic factors, e.g. ceramide level, p53 activity, bcl-2 protein levels, besides inhibiting DNA/RNA synthesis and topoisomerase-II action. We report binding of epirubicin with G-quadruplex (G4) DNA, [d-(TTAGGGT)], comprising human telomeric DNA sequence TTAGGG, using H and P NMR spectroscopy. Diffusion ordered spectroscopy, sequence selective changes in chemical shift (~0.33 ppm) and line broadening in DNA signals suggest formation of a well-defined complex. Presence of sequential nuclear Overhauser enhancements at all base quartet steps and absence of large downfield shifts in P resonances preclude intercalative mode of interaction. Restrained molecular dynamics simulations using AMBER force field incorporating intermolecular drug to DNA interproton distances, involving ring D protons of epirubicin depict external binding close to T1-T2-A3 and G6pT7 sites. Binding induced thermal stabilization of G4 DNA (~36 °C), obtained from imino protons and differential scanning calorimetry, is likely to come in the way of telomerase association with telomeres. The findings pave the way for drug-designing with modifications at ring D and daunosamine sugar.

PubMed: 32992248
DOI: 10.1016/j.bmc.2020.115761

Experimental method

SOLUTION NMR