SARS-CoV-2 Nsp16 activation mechanism and a cryptic pocket with pan-coronavirus antiviral potential.
SARS-CoV-2 Nsp16 activation mechanism and a cryptic pocket with pan-coronavirus antiviral potential.
复制标题
DOI：
10.1016/j.bpj.2021.03.024
复制
发表时间：
2021-07-20
影响因子：
3.4
通讯作者：
Bowman GR
中科院分区：
文献类型：
--
作者：
Vithani N;Ward MD;Zimmerman MI;Novak B;Borowsky JH;Singh S;Bowman GR
冠状病毒在过去二十年中引发了多次流行病，加上目前严重损害全球健康和经济的COVID-19大流行病。冠状病毒使用20至30种蛋白质来进行其病毒复制周期，包括感染、免疫逃避和复制。其中，非结构蛋白16（Nsp 16）是一种2′-O-甲基转移酶，在免疫逃避中起重要作用。Nsp 16通过模仿其人类同源物CMTr 1来实现这一点，CMTr 1甲基化mRNA以提高翻译效率并将自身与他人区分开来。与人CMTr 1不同，Nsp 16需要结合伴侣Nsp 10来激活其酶活性。这种结合伙伴的要求提出了两个问题，我们在这篇手稿中调查。Nsp 10如何激活Nsp 16？虽然存在活性Nsp 16/Nsp 10复合物的实验衍生结构，但非活性单体Nsp 16的结构尚未解决。目前还不清楚Nsp 10是如何激活Nsp 16的。利用超过1 ms的Nsp 16及其与Nsp 10的复合物的分子动力学模拟，我们研究了Nsp 10的存在如何改变Nsp 16的构象系综以激活它。其次，在这种激活机制和马尔可夫状态模型的指导下，我们研究了Nsp 16是否采用了具有隐蔽口袋的无活性结构，如果用小分子靶向，通过稳定Nsp 16的失活状态来抑制Nsp 16。在SARS-CoV 2 Nsp 16中识别出这样一个口袋后，我们发现这个隐藏的口袋也在SARS-CoV 1和MERS中打开，但在人类CMTr 1中没有打开。因此，有可能开发出靶向这种隐蔽口袋的泛冠状病毒抗病毒药物。
Coronaviruses have caused multiple epidemics in the past two decades, in addition to the current COVID-19 pandemic that is severely damaging global health and the economy. Coronaviruses employ between 20 and 30 proteins to carry out their viral replication cycle, including infection, immune evasion, and replication. Among these, nonstructural protein 16 (Nsp16), a 2′-O-methyltransferase, plays an essential role in immune evasion. Nsp16 achieves this by mimicking its human homolog, CMTr1, which methylates mRNA to enhance translation efficiency and distinguish self from other. Unlike human CMTr1, Nsp16 requires a binding partner, Nsp10, to activate its enzymatic activity. The requirement of this binding partner presents two questions that we investigate in this manuscript. First, how does Nsp10 activate Nsp16? Although experimentally derived structures of the active Nsp16/Nsp10 complex exist, structures of inactive, monomeric Nsp16 have yet to be solved. Therefore, it is unclear how Nsp10 activates Nsp16. Using over 1 ms of molecular dynamics simulations of both Nsp16 and its complex with Nsp10, we investigate how the presence of Nsp10 shifts Nsp16’s conformational ensemble to activate it. Second, guided by this activation mechanism and Markov state models, we investigate whether Nsp16 adopts inactive structures with cryptic pockets that, if targeted with a small molecule, could inhibit Nsp16 by stabilizing its inactive state. After identifying such a pocket in SARS-CoV2 Nsp16, we show that this cryptic pocket also opens in SARS-CoV1 and MERS but not in human CMTr1. Therefore, it may be possible to develop pan-coronavirus antivirals that target this cryptic pocket.
登录
查看更多内容
影响因子：
6.7
作者：
Decroly E;Debarnot C;Ferron F;Bouvet M;Coutard B;Imbert I;Gluais L;Papageorgiou N;Sharff A;Bricogne G;Ortiz-Lombardia M;Lescar J;Canard B
通讯作者：
Canard B
影响因子：
--
作者：
Belete, Tafere Mulaw
通讯作者：
Belete, Tafere Mulaw
影响因子：
5.5
作者：
Hess, Berk
通讯作者：
Hess, Berk
病毒mRNA帽的2'-O甲基化通过IFIT家族成员逃避了宿主的限制。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML