Structural recognition of the MYC promoter G-quadruplex by a quinoline derivative: Insights into molecular targeting of parallel G-quadruplexes
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College of Pharmacy, The University of ArizonaIssue Date
2021
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Oxford University PressCitation
Dickerhoff, J., Dai, J., & Yang, D. (2021). Structural recognition of the MYC promoter G-quadruplex by a quinoline derivative: Insights into molecular targeting of parallel G-quadruplexes. Nucleic Acids Research, 49(10), 5905–5915.Journal
Nucleic Acids ResearchRights
Copyright © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/).Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
DNA G-Quadruplexes (G4s) formed in oncogene promoters regulate transcription. The oncogene MYC promoter G4 (MycG4) is the most prevalent G4 in human cancers. However, the most studied MycG4 sequence bears a mutated 3′-residue crucial for ligand recognition. Here, we report a new drug-like small molecule PEQ without a large aromatic moiety that specifically binds MycG4. We determined the NMR solution structures of the wild-type MycG4 and its 2:1 PEQ complex, as well as the structure of the 2:1 PEQ complex of the widely used mutant MycG4. Comparison of the two complex structures demonstrates specific molecular recognition of MycG4 and shows the clear effect of the critical 3′-mutation on the drug binding interface. We performed a systematic analysis of the four available complex structures involving the same mutant MycG4, which can be considered a model system for parallel G4s, and revealed for the first time that the flexible flanking residues are recruited in a conserved and sequence-specific way, as well as unused potential for selective ligand-G4 hydrogen-bond interactions. Our results provide the true molecular basis for MycG4-targeting drugs and new critical insights into future rational design of drugs targeting MycG4 and parallel G4s that are prevalent in promoter and RNA G4s. © 2021 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.Note
Open access journalISSN
0305-1048PubMed ID
33978746Version
Final published versionae974a485f413a2113503eed53cd6c53
10.1093/nar/gkab330
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Except where otherwise noted, this item's license is described as Copyright © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/).
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