Crystal structure of SARS-CoV-2 main protease in complex with the natural product inhibitor shikonin illuminates a unique binding mode.
Crystal structure of SARS-CoV-2 main protease in complex with the natural product inhibitor shikonin illuminates a unique binding mode.
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SARS-CoV-2主要蛋白酶与天然产物抑制剂紫草素复合物的晶体结构阐明了独特的结合模式
DOI：
10.1016/j.scib.2020.10.018
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发表时间：
2021-04-15
期刊：
影响因子：
18.9
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Li J;Zhou X;Zhang Y;Zhong F;Lin C;McCormick PJ;Jiang F;Luo J;Zhou H;Wang Q;Fu Y;Duan J;Zhang J
几乎每个人都容易感染严重急性呼吸综合征冠状病毒2（SARS-CoV-2），这是一种RNA病毒，可导致许多症状，甚至在高危人群中死亡[1，2]。主要蛋白酶（Mpro，也称为3CLpro）是产生感染性病毒体所必需的半胱氨酸蛋白酶，因此是药物开发的有吸引力的靶标。到目前为止，已经进行了许多使用计算机模拟配体对接或基于可用结构的药物发现的研究，以发现新的Mpro抑制剂[3，4]。然而，大多数研究使用肽模拟物或Mpro的共价抑制剂，这可能会引入与宿主蛋白的非特异性反应。在这里，我们展示了与Mpro非共价结合构型的紫草素结构，并将其与共价键合结构进行比较，以寻求能够抑制主要蛋白酶的新型支架。如图1所示，Mpro与紫草素复合物（ShiMpro）的晶体结构在2.45 nm处解析（图1a和在线表S1），紫草素仅与其中一种原聚体（即原聚体A）结合，尽管它们的整体结构相似（图S1在线，补充材料和方法在线）。ShiMpro显示与pH 7.5时Mpro的apo结构（apoMpro）相同的总体折叠[5]。apo和ShiMpro之间等效Ca位置的均方根（RMS）差约为0.3 μ m（图1b）。ShiMpro结构与先前解出的相邻结合结构的叠加显示出高度的空间守恒性（图1b和在线图S2）。抑制剂结合口袋被S1-S4亚位点包围，紫草素与它们形成多重相互作用（图1b）。首先，紫草素与位于S1亚位点的蛋白酶极性三联体Cys 145和His 164形成氢键网络。第二，紫草素的芳香族头基与S2亚位点上的His 41形成p-p相互作用。第三，紫草素尾部异己烯基侧链的羟基和甲基分别与S3亚位上的Arg 188和Gln 189形成氢键。
Almost everyone is susceptible to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus, which can cause many symptoms and even death among high-risk individuals [1, 2]. The main protease (Mpro, also known as 3CLpro) is a cysteine protease essential for producing infectious virions and thus, an attractive target for drug development. Up to now, many studies using either in silico ligand docking or drug discovery based on available structures have been performed to discover new Mproinhibiting agents [3, 4]. However, most studies have used either peptidomimetics or covalent inhibitors for Mpro, which may introduce non-specific reactions with host proteins. Here, we presented the structure of shikonin in a non-covalent binding configuration with Mpro and compared it with covalent bonding structures in pursuit of novel scaffolds capable of inhibiting the main protease. As shown in Fig. 1, the crystal structure of Mpro in complex with shikonin (ShiMpro) is resolved at 2.45 Å (Fig. 1a and Table S1 online), and shikonin binds to only one of the protomers (ie, protomer A) despite their overall structural similarity (Fig. S1 online, Supplementary materials and methods online). ShiMpro shows the same overall fold as for the apo structure of Mpro at pH 7.5 (apoMpro)[5]. The root mean square (RMS) difference of equivalent Ca positions between apo and ShiMpro is~ 0.3 Å (Fig. 1b).An overlay of the ShiMpro structure with the previously solved inhibitor-bound structures shows high spatial conservation (Fig. 1b and Fig. S2 online). The inhibitor binding pocket is surrounded by S1–S4 subsites, and shikonin forms multiple interactions with them (Fig. 1b). First, shikonin forms a hydrogen bond network with the protease polar triad Cys145 and His164 located on the S1 subsite. Second, the aromatic head groups of shikonin form a p-p interaction with His41 on the S2 subsite. Third, the hydroxy and methyl group of the isohexenyl side chain of shikonin tail form H-bonding with Arg188 and Gln189 on the S3 subsite, respectively.
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