Residue-Orientation-Dependent Dynamics and Selectivity of Active Pocket in Microbe Class I Terpene Cyclases
Residue-Orientation-Dependent Dynamics and Selectivity of Active Pocket in Microbe Class I Terpene Cyclases
复制标题
微生物 I 类萜烯环化酶中活性袋的残基方向依赖性动力学和选择性
DOI：
10.1021/acs.jcim.0c00159
复制
发表时间：
2020-08
影响因子：
5.6
通讯作者：
Wu Ruibo
中科院分区：
文献类型：
--
作者：
Zhuang Jingyuan;Zhang Fan;Zhou Jingwei;Deng Wenbin;Wu Ruibo
微生物 I 类萜烯环化酶 (TPC) 负责衍生出众多功能和结构多样的萜类天然产物。其活性口袋在底物结合时从“开放”状态到“闭合”状态的构象变化已被阐明。然而，与这种活性口袋动力学相关的关键结构基础及其详细的分子机制仍不清楚。在这项工作中，基于两种微生物 I 类 TPC（SdS 和 bCinS）的分子动力学（MD），我们提出活性口袋动力学高度依赖于两个保守结构碱基 R-D 二联体和 X-R-D 三联体的残基方向，而不是之前提出的扭结区域的灵活性。实际上，我们认为扭结区的柔性与X-R-D三元组的R残基方向同步，可以利用X-R-D三元组的混杂性来调节活性口袋的入口尺寸，从而影响活性口袋的底物选择性。此外，为了更好地理解这两个结构基础的功能，提出了“PPi catcher-locker”和“selector-PPisensor-orienter”两种可理解的模型来分别描述R-D二元组和X-R-D三元组，并扩展到更多的微生物I类TPC。这些发现展示了静态晶体结构中难以接近的活性口袋的动力学，并为进一步设计具有不同环化能力的微生物I类TPC提供了有用的结构基础知识。
Microbe class I terpene cyclases (TPCs) are responsible for deriving numerous functionally and structurally diverse groups of terpenoids natural products. The conformational change of their active pockets from "open" state to "closed" state upon substrate binding has been clarified. However, the key structural basis relevant to this active pocket dynamics and its detailed molecular mechanism are still unclear. In this work, on the basis of the molecular dynamics (MD) on two microbe class I TPCs (SdS and bCinS), we propose that the active pocket dynamics is highly dependent on the residue orientation of two conserved structural bases R-D dyad and X-R-D triad, rather than the previously suggested flexibility of kink region. Actually, we considered that the flexibility of kink region is synchronous with the R residue orientation of X-R-D triad, which could regulate the entrance size of active pocket and thus affect the substrate selectivity of active pocket by utilizing the promiscuity of X-R-D triad. Furthermore, to better understand the function of the two structural bases, two intelligible models of "PPi catcher-locker" and "selector-PPi sensor-orienter" are proposed to respectively describe the R-D dyad and X-R-D triad, and broadened to more microbe class I TPCs. These findings exhibit the dynamics of active pocket inaccessible in static crystal structures, and provide useful structural basis knowledge for further design of microbe class I TPCs with different cyclization ability.
登录
查看更多内容
影响因子：
2.9
作者：
Li R;Chou WK;Himmelberger JA;Litwin KM;Harris GG;Cane DE;Christianson DW
通讯作者：
Christianson DW
影响因子：
2.9
作者：
Blank PN;Barrow GH;Chou WKW;Duan L;Cane DE;Christianson DW
通讯作者：
Christianson DW
影响因子：
16.6
作者：
Oldfield, Eric;Lin, Fu-Yang
通讯作者：
Lin, Fu-Yang
影响因子：
2.9
作者：
Rynkiewicz, MJ;Cane, DE;Christianson, DW
通讯作者：
Christianson, DW
影响因子：
2.9
作者：
L. Vedula;M. Rynkiewicz;H. Pyun;R. Coates;D. Cane;D. Christianson
通讯作者：
L. Vedula;M. Rynkiewicz;H. Pyun;R. Coates;D. Cane;D. Christianson