Human telomeric DNA forms parallel-stranded intramolecular G-quadruplex in K+ solution under molecular crowding condition.
Human telomeric DNA forms parallel-stranded intramolecular G-quadruplex in K+ solution under molecular crowding condition.
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人端粒DNA在分子拥挤条件下在K溶液中形成平行链分子内G-四链体。
DOI：
10.1021/ja0730462
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发表时间：
2007-08
影响因子：
15
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中科院分区：
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人端粒DNA的富含G的链可以折叠成称为G-四链体的四链结构，并抑制端粒酶活性，端粒酶活性在85-90%的肿瘤细胞中表达。由于这个原因，端粒四链体正在成为癌症的潜在治疗靶点。四链体在生理环境中的结构信息对于靶向四链体的基于结构的药物设计非常重要。最近的研究已经提出了重大的争议，在生理相关的环境中由人类端粒DNA形成的四链体的确切结构。对在K+溶液中制备的晶体的研究揭示了独特的螺旋桨形平行链构象。然而，许多后来的工作未能确认这种结构在生理K+溶液，而是导致了不同的杂交型混合平行/反平行四链体的鉴定。在这里，我们表明，人端粒DNA在生理K+溶液中采用平行链构象下的分子拥挤的PEG条件下创建的。在40%（w/v）的浓度下，PEG诱导完全结构转化为平行链的G-四链体。我们还表明，在这种条件下形成的四链体具有不寻常的稳定性和显着的负面影响端粒酶的持续性。由于细胞内的环境是分子拥挤的，我们在模拟细胞的条件下获得的结果表明，平行链的四链体可能是在生理条件下更有利的结构，靶向人类端粒四链体的药物设计应该考虑到这一点。
The G-rich strand of human telomeric DNA can fold into a four-stranded structure called G-quadruplex and inhibit telomerase activity that is expressed in 85-90% tumor cells. For this reason, telomere quadruplex is emerging as a potential therapeutic target for cancer. Information on the structure of the quadruplex in the physiological environment is important for structure-based drug design targeting the quadruplex. Recent studies have raised significant controversy regarding the exact structure of the quadruplex formed by human telomeric DNA in a physiological relevant environment. Studies on the crystal prepared in K+ solution revealed a distinct propeller-shaped parallel-stranded conformation. However, many later works failed to confirm such structure in physiological K+ solution but rather led to the identification of a different hybrid-type mixed parallel/antiparallel quadruplex. Here we demonstrate that human telomere DNA adopts a parallel-stranded conformation in physiological K+ solution under molecular crowding conditions created by PEG. At the concentration of 40% (w/v), PEG induced complete structural conversion to a parallel-stranded G-quadruplex. We also show that the quadruplex formed under such a condition has unusual stability and significant negative impact on telomerase processivity. Since the environment inside cells is molecularly crowded, our results obtained under the cell mimicking condition suggest that the parallel-stranded quadruplex may be the more favored structure under physiological conditions, and drug design targeting the human telomeric quadruplex should take this into consideration.