Conformational dynamics of RNA G4C2 and G2C4 repeat expansions causing ALS/FTD using NMR and molecular dynamics studies.
Conformational dynamics of RNA G4C2 and G2C4 repeat expansions causing ALS/FTD using NMR and molecular dynamics studies.
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DOI：
10.1093/nar/gkad403
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发表时间：
2023-06-23
影响因子：
14.9
通讯作者：
中科院分区：
文献类型：
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作者：
9号染色体开放阅读框72(C9orf72)上的G4C2和G2C4重复扩增是遗传性肌萎缩侧索硬化症(ALS)和额颞痴呆(FTD)或C9ALS/FTD的最常见原因。该基因是双向转录的，产生G4C2重复[r(G4C2)EXP]和G2C4重复[r(G2C4)EXP]。C9ALS/FTD重复序列的扩展是高度结构化的，结构研究表明r(G4C2)exp主要折叠成一个发夹，具有1×1G/G内环和G-四链的周期性阵列。小分子探针显示，r(G4C2)EXP也采用发夹结构，内环为2×2 GG/GG。我们用温度副本交换分子动力学(T-REMD)研究了2×2 GG/GG环的构象动力学，并用传统的2D核磁共振技术进一步表征了结构和潜在的动力学。这些研究表明，环的闭合碱基对影响结构和动力学，特别是糖苷键周围的构型。有趣的是，r(G2C4)重复序列折叠成2×2个CC/CC内部循环的数组，不是那么动态的。总之，这些研究强调了r(G4C2)EXP对堆积相互作用的微小变化的独特敏感性，这在r(G2C4)EXP中没有观察到，这为基于结构的药物设计的进一步原则提供了重要的考虑。
G4C2 and G2C4 repeat expansions in chromosome 9 open reading frame 72 (C9orf72) are the most common cause of genetically defined amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), or c9ALS/FTD. The gene is bidirectionally transcribed, producing G4C2 repeats [r(G4C2)exp] and G2C4 repeats [r(G2C4)exp]. The c9ALS/FTD repeat expansions are highly structured, and structural studies showed that r(G4C2)exp predominantly folds into a hairpin with a periodic array of 1 × 1 G/G internal loops and a G-quadruplex. A small molecule probe revealed that r(G4C2)exp also adopts a hairpin structure with 2 × 2 GG/GG internal loops. We studied the conformational dynamics adopted by 2 × 2 GG/GG loops using temperature replica exchange molecular dynamics (T-REMD) and further characterized the structure and underlying dynamics using traditional 2D NMR techniques. These studies showed that the loop's closing base pairs influence both structure and dynamics, particularly the configuration adopted around the glycosidic bond. Interestingly, r(G2C4) repeats, which fold into an array of 2 × 2 CC/CC internal loops, are not as dynamic. Collectively, these studies emphasize the unique sensitivity of r(G4C2)exp to small changes in stacking interactions, which is not observed in r(G2C4)exp, providing important considerations for further principles in structure-based drug design.
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DOI：
10.1038/s41580-019-0136-0
发表时间：
2019-08
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Ganser LR;Kelly ML;Herschlag D;Al-Hashimi HM
通讯作者：
Al-Hashimi HM
影响因子：
3.3
作者：
Havrila, Marek;Zgarbova, Marie;Sponer, Jiri
通讯作者：
Sponer, Jiri
影响因子：
64.8
作者：
Houck-Loomis, Brian;Durney, Michael A.;Salguero, Carolina;Shankar, Neelaabh;Nagle, Julia M.;Goff, Stephen P.;D'Souza, Victoria M.
通讯作者：
D'Souza, Victoria M.
影响因子：
14.8
作者：
Baisden, Jared T.;Boyer, Joshua A.;Zhang, Qi
通讯作者：
Zhang, Qi
影响因子：
2.9
作者：
Dodd, David W.;Tomchick, Diana R.;Gagnon, Keith T.
通讯作者：
Gagnon, Keith T.