期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 27, 期 3, 页码 1113-1121出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202004040
关键词
allosterism; binding mechanisms; G-quadruplexes; mass spectrometry; orthosterism; proteins
资金
- Swiss National Science Foundation [200020-178765]
This study investigated ternary G4:L:P complexes using native mass spectrometry, finding that RHAU preferentially binds to parallel G4s and free external G-quartets. The ligands were observed to prevent peptide binding by direct competition or inducing conformational changes, with Cu-ttpy even increasing peptide binding through a conformational change.
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.
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