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Piece of the puzzle: Remdesivir disassembles the multimeric SARS-CoV-2 RNA-dependent RNA polymerase complex
Cell Biochemistry and Biophysics ( IF 2.6 ) Pub Date : 2021-04-01 , DOI: 10.1007/s12013-021-00977-y
Fisayo A Olotu 1 , Kehinde F Omolabi 1 , Mahmoud E S Soliman 1
Affiliation  

The recently emerged SARS-like coronavirus (SARS-CoV-2) has continued to spread rapidly among humans with alarming upsurges in global mortality rates. A major key to tackling this virus is to disrupt its RNA replication process as previously reported for Remdesivir (Rem-P3). In this study, we theorize, using computational simulations, novel mechanisms that may underlie the binding of Rem-P3 to SARS-CoV-2 RdRp-NSPs complex; a multimeric assembly that drives viral RNA replication in human hosts. Findings revealed that while ATP-binding stabilized the replicative tripartite, Rem-P3 disintegrated the RdRp-NSP complex, starting with the detachment of the NSP7-NSP8 heterodimer followed by minimal displacement of the second NSP8 subunit (NSP8II). More so, Rem-P3 interacted with a relatively higher affinity (ΔGbind) while inducing high perturbations across the RdRp-NSP domains. D452, T556, V557, S682, and D760 were identified for their crucial roles in stacking the cyano-adenosine and 3,4-dihydroxyoxolan rings of Rem-P3 while its flexible P3 tail extended towards the palm domain blocking D618 and K798; a residue-pair identified for essential roles in RNA replication. However, ATP folded away from D618 indicative of a more coordinated binding favorable for nucleotide polymerization. We believe findings from this study will significantly contribute to the structure-based design of novel disruptors of the SARS-CoV-2 RNA replicative machinery.



中文翻译:

拼图的一部分:瑞德西韦分解了多聚体 SARS-CoV-2 RNA 依赖性 RNA 聚合酶复合物

最近出现的类 SARS 冠状病毒 (SARS-CoV-2) 继续在人类中迅速传播,全球死亡率上升令人震惊。对付这种病毒的一个主要关键是破坏它的 RNA 复制过程,正如之前报道的瑞德西韦 ( Rem -P 3 )。在这项研究中,我们使用计算模拟对可能构成Rem -P 3与 SARS-CoV-2 RdRp-NSPs 复合物结合的新机制进行了理论化;在人类宿主中驱动病毒 RNA 复制的多聚体组装。研究结果表明,虽然 ATP 结合稳定了复制三方,但Rem -P 3分解 RdRp-NSP 复合物,从 NSP7-NSP8 异二聚体的分离开始,然后是第二个 NSP8 亚基 (NSP8 II ) 的最小置换。更重要的是,Rem -P 3与相对较高的亲和力(ΔG结合)相互作用,同时在 RdRp-NSP 结构域中诱导高扰动。D452、T556、V557、S682 和 D760 在堆叠Rem -P 3的氰基-腺苷和 3,4-二羟基氧杂环戊烷环中发挥关键作用,而其灵活的 P 3尾巴向掌域延伸,挡住 D618 和 K798;确定在 RNA 复制中起重要作用的残基对。然而,ATP 折叠远离 D618,表明更协调的结合有利于核苷酸聚合。我们相信,这项研究的结果将大大有助于基于结构的 SARS-CoV-2 RNA 复制机制新型破坏物的设计。

更新日期:2021-04-01
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