DSSR-PyMOL cartoon-block schematics: PDB entry 6neb

PDB-id

6neb; DSSR-derived features in text and JSON formats

Class

DNA

Method

NMR

Summary

Myc promoter g-quadruplex with 1:6:1 loop length

Reference

Dickerhoff J, Onel B, Chen L, Chen Y, Yang D (2019): "Solution Structure of a MYC Promoter G-Quadruplex with 1:6:1 Loop Length." Acs Omega, 4, 2533-2539. doi: 10.1021/acsomega.8b03580.

Abstract

The important <i>MYC</i> oncogene is deregulated in many cancer cells and comprises one of the most prominent G-quadruplex (G4) forming sequences in its promoter regions, the NHE III₁ motif. Formation of G4s suppresses <i>MYC</i> transcription and can be modulated by drug binding, establishing these DNA structures as promising targets in cancer therapy. The NHE III₁ motif can fold into more than one parallel G4s, including 1:2:1 and 1:6:1 loop length conformers, with the 1:2:1 conformer shown as the major species under physiological conditions in solution. However, additional factors such as protein interactions may affect the cellular folding equilibrium. Nucleolin, a protein shown to bind <i>MYC</i> G4 and repress <i>MYC</i> transcription, is reported herein to preferably bind to the 1:6:1 loop length conformer suggesting a physiological significance of this species. The high-resolution NMR solution structure of the 1:6:1 conformer is determined, which reveals a 5'-capping structure distinctive from the 1:2:1 form, with the 6 nt central loop playing an essential role for this specific capping structure. This suggests that each parallel G-quadruplex likely adopts unique capping and loop structures determined by the specific central loop and flanking sequences. The resulting structural information at the molecular level will help to understand protein recognition of different G4s, contribution of G4 polymorphism to gene regulation, and to rationally design small molecules selectively targeting the 1:6:1 <i>MYC</i> G4.