Allosteric Regulation of 3CL Protease of SARS-CoV-2 and SARS-CoV Observed in the Crystal Structure Ensemble.
Allosteric Regulation of 3CL Protease of SARS-CoV-2 and SARS-CoV Observed in the Crystal Structure Ensemble.
复制标题
DOI：
10.1016/j.jmb.2021.167324
复制
发表时间：
2021-12-03
影响因子：
5.6
通讯作者：
Ikeguchi M
中科院分区：
文献类型：
--
作者：
Kidera A;Moritsugu K;Ekimoto T;Ikeguchi M
SARS-CoV-2 的 3C 样蛋白酶 (3CLpro) 是 COVID-19 的潜在治疗靶点。重要的是，它具有丰富的结构信息，可与各种候选药物化合物形成复合物。通过收集这些晶体结构（83 个蛋白质数据库（PDB）条目）以及 SARS-CoV 高度同源的 3CLpro 的晶体结构（101 个 PDB 条目），我们构建了 3CLpro 的晶体结构整体，以分析其催化功能的动态调节。在整体中观察到的 3CLpro 二聚体的结构动力学特征是四个独立环（C 环、E 环、H 环和连接体）和胰凝乳蛋白酶折叠刚性核心上的 C 末端结构域 III 的运动。在四个移动环中，C环（也称为氧阴离子结合环）引起有序（活性）-无序（塌陷）转变，该转变受到与周围残基形成的五个氢键的协同调节。 C 环、E 环和接头构成主要的配体结合位点，其由有限种类的结合残基组成，包括底物结合亚位点。配体结合导致 E 环和连接体发生配体大小依赖性构象变化，从而通过 C 环和 E 环之间的氢键进一步稳定 C 环。从 SARS-CoV 3CLpro 到 SARS-CoV-2 3CLpro 的 T285A 突变显着关闭了结构域 III 二聚体的界面，并通过与 Ser1 和 Gly2 的氢键变构稳定了 C 环的活性构象；因此，相对于 SARS-CoV 3CLpro，SARS-CoV-2 3CLpro 的活性似乎有所增加。
The 3C-like protease (3CLpro) of SARS-CoV-2 is a potential therapeutic target for COVID-19. Importantly, it has an abundance of structural information solved as a complex with various drug candidate compounds. Collecting these crystal structures (83 Protein Data Bank (PDB) entries) together with those of the highly homologous 3CLpro of SARS-CoV (101 PDB entries), we constructed the crystal structure ensemble of 3CLpro to analyze the dynamic regulation of its catalytic function. The structural dynamics of the 3CLpro dimer observed in the ensemble were characterized by the motions of four separate loops (the C-loop, E-loop, H-loop, and Linker) and the C-terminal domain III on the rigid core of the chymotrypsin fold. Among the four moving loops, the C-loop (also known as the oxyanion binding loop) causes the order (active)–disorder (collapsed) transition, which is regulated cooperatively by five hydrogen bonds made with the surrounding residues. The C-loop, E-loop, and Linker constitute the major ligand binding sites, which consist of a limited variety of binding residues including the substrate binding subsites. Ligand binding causes a ligand size dependent conformational change to the E-loop and Linker, which further stabilize the C-loop via the hydrogen bond between the C-loop and E-loop. The T285A mutation from SARS-CoV 3CLpro to SARS-CoV-2 3CLpro significantly closes the interface of the domain III dimer and allosterically stabilizes the active conformation of the C-loop via hydrogen bonds with Ser1 and Gly2; thus, SARS-CoV-2 3CLpro seems to have increased activity relative to that of SARS-CoV 3CLpro.
登录
查看更多内容
冠状病毒主蛋白酶的结构揭示了甲over依蛋白酶折叠与额外的α-螺旋结构域的组合。
影响因子：
11.4
作者：
Anand, Kanchan;Palm, Gottfried J;Mesters, Jeroen R;Siddell, Stuart G;Ziebuhr, John;Hilgenfeld, Rolf
通讯作者：
Hilgenfeld, Rolf
影响因子：
2.9
作者：
Chou, CY;Chang, HC;Chang, GG
通讯作者：
Chang, GG
影响因子：
3.3
作者：
Kobayashi, Chigusa;Matsunaga, Yasuhiro;Sugita, Yuji
通讯作者：
Sugita, Yuji
影响因子：
2.9
作者：
Barrila, Jennifer;Gabelli, Sandra B.;Bacha, Usman;Amzel, L. Mario;Freire, Ernesto
通讯作者：
Freire, Ernesto
底物样的AZA肽环氧化物抑制了SARS冠状病毒的主要肽酶的晶体结构。
影响因子：
5.6
作者：
Lee TW;Cherney MM;Huitema C;Liu J;James KE;Powers JC;Eltis LD;James MN
通讯作者：
James MN