Competition of Ligands and the 18‐mer Binding Domain of the RHAU Helicase for G‐Quadruplexes: Orthosteric or Allosteric Binding Mechanism?
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Date
2021-01-13
Publication Type
Journal Article
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yes
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Abstract
Stabilizing the DNA and RNA structures known as G‐quadruplexes (G4s) using specific ligands is a strategy that has been proposed to fight cancer. However, although G‐quadruplex:ligand (G4:L) interactions have often been investigated, whether or not ligands are able to disrupt G‐quadruplex:protein (G4:P) interactions remains poorly studied. In this study, using native mass spectrometry, we have investigated ternary G4:L:P complexes formed by G4s, some of the highest affinity ligands, and the binding domain of the RHAU helicase. Our results suggest that RHAU binds not only preferentially to parallel G4s, but also to free external G‐quartets. We also found that, depending on the G4, ligands could prevent the binding of the peptide, either by direct competition for the binding sites (orthosteric inhibition) or by inducing conformational changes (allosteric inhibition). Notably, the ligand Cu–ttpy (ttpy=4′‐tolyl‐2,2′:6′,2′′‐terpyridine) induced a conformational change that increased the binding of the peptide. This study illustrates that it is important to not only characterize drug–target interactions, but also how the binding to other partners is affected. © 2020 Wiley‐VCH GmbH.
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published
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Journal / series
Volume
27 (3)
Pages / Article No.
1113 - 1121
Publisher
Wiley-VCH
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Subject
Allosterism; Binding mechanisms; G-quadruplexes; Mass spectrometry; Orthosterism; Proteins
Organisational unit
03430 - Zenobi, Renato / Zenobi, Renato
Notes
Funding
178765 - Soft ionization mass spectrometry for studying noncovalent interactions (SNF)