pH-driven conformational switch between non-canonical DNA structures in a C-rich domain of EGFR promoter
pH-driven conformational switch between non-canonical DNA structures in a C-rich domain of EGFR promoter
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DOI：
10.1038/s41598-018-37968-8
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发表时间：
2019-02-04
影响因子：
4.6
通讯作者：
Sissi, Claudia
中科院分区：
文献类型：
--
作者：
Cristofari, Camilla;Rigo, Riccardo;Sissi, Claudia
EGFR 是一种编码跨膜酪氨酸激酶受体的癌基因。它的错误调节与多种人类癌症有关，而这些癌症始终可以通过选择性酪氨酸激酶抑制剂来治疗。 EGFR 的近端启动子包含一个富含 G 的结构域，位于转录起始位点上游 272 个碱基处。我们之前证明它可以折叠成两种主要的互换 G-四联体结构，一种是并行拓扑，一种是混合拓扑。在这里，我们提出了第一个证据，支持互补的富含 C 链 (EGFR-272_C) 具有分子内 i-Motif (iM) 结构的能力，根据实验条件（pH、共溶剂和盐的存在），该结构可以与我们称为发夹的不同排列共存。本文鉴定的 iM 有效地与两条互补链的规范配对竞争，表明它是抗癌治疗的潜在新靶标。对潜在结合物的初步筛选发现，一些菲咯啉衍生物在折叠成 iM 时能够在多个结合位点靶向 EGFR-272_C。
EGFR is an oncogene that encodes for a trans-membrane tyrosine kinase receptor. Its mis-regulation is associated to several human cancers that, consistently, can be treated by selective tyrosine kinase inhibitors. The proximal promoter of EGFR contains a G-rich domain located at 272 bases upstream the transcription start site. We previously proved it folds into two main interchanging G-quadruplex structures, one of parallel and one of hybrid topology. Here we present the first evidences supporting the ability of the complementary C-rich strand (EGFR-272_C) to assume an intramolecular i-Motif (iM) structure that, according to the experimental conditions (pH, presence of co-solvent and salts), can coexist with a different arrangement we referred to as a hairpin. The herein identified iM efficiently competes with the canonical pairing of the two complementary strands, indicating it as a potential novel target for anticancer therapies. A preliminary screening for potential binders identified some phenanthroline derivatives as able to target EGFR-272_C at multiple binding sites when it is folded into an iM.