Crystal structure of the major quadruplex formed in the promoter region of the human c-MYC oncogene

Stump, Sascha; Mou, Tung-Chung; Sprang, Stephen R.; Natale, Nicholas R.; Beall, Howard D.

doi:10.1371/journal.pone.0205584

Crystal structure of the major quadruplex formed in the promoter region of the human c-MYC oncogene

Journal Article · Fri Oct 12 00:00:00 EDT 2018 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0205584· OSTI ID:1627869

Stump, Sascha ^[1]; Mou, Tung-Chung ^[2]; Sprang, Stephen R. ^[2]; ^[2]; ^[2]

Univ. of Montana, Missoula, MT (United States); DOE/OSTI
Univ. of Montana, Missoula, MT (United States)

The c-MYC oncogene mediates multiple tumor cell survival pathways and is dysregulated or overexpressed in the majority of human cancers. The NHE III₁ region of the c-MYC promoter forms a DNA quadruplex. Stabilization of this structure with small molecules has been shown to reduce expression of c-MYC, and targeting the c-MYC quadruplex has become an emerging strategy for development of antitumor compounds. Previous solution NMR studies of the c-MYC quadruplex have assigned the major conformer and topology of this important target, however, regions outside the G-quartet core were not as well-defined. Here, we report a high-resolution crystal structure (2.35 Å) of the major quadruplex formed in the NHE III₁ region of the c-MYC promoter. The crystal structure is in general agreement with the solution NMR structure, however, key differences are observed in the position of nucleotides outside the G-quartet core. The crystal structure provides an alternative model that, along with comparisons to other reported quadruplex crystal structures, will be important to the rational design of selective compounds. This work will aid in development of ligands to target the c-MYC promoter quadruplex with the goal of creating novel anticancer therapies.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Lab., Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1627869

Journal Information:: PLoS ONE, Journal Name: PLoS ONE Journal Issue: 10 Vol. 13; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
Crystal structure
Crystallization
Guanine
Nucleotides
Oligonucleotides
Oncogenes
Potassium
Small molecules

Crystal structure of the major quadruplex formed in the promoter region of the human c-MYC oncogene

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References (54)

Cited By (5)

Figures / Tables (10)

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