Cooperative Heteroligand Interaction with G-Quadruplexes Shows Evidence of Allosteric Binding.,Biochemistry

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Cooperative Heteroligand Interaction with G-Quadruplexes Shows Evidence of Allosteric Binding.
Biochemistry ( IF 2.9 ) Pub Date : 2020-08-24 , DOI: 10.1021/acs.biochem.0c00351
Shankar Pandey ₁ , Yuanyuan Li _{1,

2} , Montwaun D Young ₃ , Shankar Mandal ₁ , Laichun Lu ₄ , Jacob T Shelley ₃ , Hanbin Mao ₁

Affiliation

Although allosteric binding of small molecules is commonplace in protein structures, it is rather rare in DNA species such as G-quadruplexes. By using CD melting, here, we found binding of the small-molecule ligands PDS and L2H2–6OTD to the telomeric DNA G-quadruplex was cooperative. Mass spectrometry indicated a 1:1:1 ratio in the ternary binding complex of the telomeric G-quadruplex, PDS, and L2H2–6OTD. Compared to the binding of each individual ligand to the G-quadruplex, single-molecule mechanical unfolding assays revealed a significantly decreased dissociation constant when one ligand is evaluated in the presence of another. This demonstrates that cooperative binding of PDS and L2H2–6OTD to the G-quadruplex is allosteric, which is also supported by the mass spectra data that indicated the ejection of coordinated sodium ions upon binding of the heteroligands to the G-quadruplex. The unprecedented observation of the allosteric ligand binding to higher-ordered structures of DNA may help to design more effective ligands to target non-B DNA species involved in many critical cellular processes.

中文翻译：

异配体与 G-四链体的协同相互作用显示了变构结合的证据。

尽管小分子的变构结合在蛋白质结构中很常见，但在 G-四链体等 DNA 物种中却相当罕见。通过使用 CD 熔解，我们发现小分子配体 PDS 和 L2H2-6OTD 与端粒 DNA G 四链体的结合是协同的。质谱分析显示端粒 G-四链体、PDS 和 L2H2-6OTD 的三元结合复合物的比例为 1:1:1。与每个配体与 G-四链体的结合相比，单分子机械解折叠分析表明，当一种配体在另一种配体存在的情况下进行评估时，解离常数显着降低。这表明 PDS 和 L2H2-6OTD 与 G-四链体的协同结合是变构的，这也得到了质谱数据的支持，该数据表明异配体与 G-四链体结合时会喷射协调的钠离子。对变构配体与 DNA 高阶结构结合的前所未有的观察可能有助于设计更有效的配体来靶向参与许多关键细胞过程的非 B DNA 物种。

更新日期：2020-09-22

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