Dickerhoff Jonathan, Haase Linn, Langel Walter, Weisz Klaus
Institute of Biochemistry, Ernst-Moritz-Arndt University Greifswald , Felix-Hausdorff-Str. 4, D-17487 Greifswald, Germany.
ACS Chem Biol. 2017 May 19;12(5):1308-1315. doi: 10.1021/acschembio.6b01096. Epub 2017 Mar 27.
A human telomere sequence that folds into an intramolecular (3 + 1)-hybrid G-quadruplex was modified by the incorporation of 2'-fluoro-2'-deoxyriboguanosines (G) into syn positions of its outer tetrad. A circular dichroism and NMR spectral analysis reveals a nearly quantitative switch of the G-tetrad polarity with concerted syn↔anti transitions of all four G residues. These observations follow findings on a G-substituted (3 + 1)-hybrid quadruplex with a different fold, suggesting a more general propensity of hybrid-type quadruplexes to undergo a tetrad polarity reversal. Two out of the three G analogs in both modified quadruplexes adopt an S-type sugar pucker, challenging a sole contribution of N-type sugars in enforcing an anti glycosidic torsion angle associated with the tetrad flip. NMR restrained three-dimensional structures of the two substituted quadruplexes reveal a largely conserved overall fold but significant rearrangements of the overhang and loop nucleotides capping the flipped tetrad. Sugar pucker preferences of the G analogs may be rationalized by different orientations of the fluorine atom and its resistance to be positioned within the narrow groove with its highly negative electrostatic potential and spine of water molecules.
一种能折叠成分子内（3 + 1）杂交G-四链体的人类端粒序列，通过将2'-氟-2'-脱氧核糖鸟苷（G）掺入其外部四联体的顺式位置进行了修饰。圆二色光谱和核磁共振光谱分析表明，随着所有四个G残基协同的顺式↔反式转变，G-四联体极性几乎发生了定量切换。这些观察结果与具有不同折叠方式的G取代（3 + 1）杂交四链体的研究结果一致，表明杂交型四链体更普遍地倾向于发生四联体极性反转。在两种修饰的四链体中，三个G类似物中有两个采用S型糖环构象，这对N型糖在强制与四联体翻转相关的反式糖苷扭转角方面的唯一贡献提出了挑战。两种取代四链体的核磁共振受限三维结构显示，整体折叠在很大程度上是保守的，但覆盖翻转四联体的突出端和环核苷酸有显著重排。G类似物的糖环构象偏好可以通过氟原子的不同取向及其在具有高度负静电势和水分子链的窄沟内定位的阻力来解释。
