Conformational Analysis of the Mannosidase Inhibitor Kifunensine: A Quantum Mechanical and Structural Approach
Conformational Analysis of the Mannosidase Inhibitor Kifunensine: A Quantum Mechanical and Structural Approach
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DOI：
10.1002/cbic.201700166
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发表时间：
2017-08-04
期刊：
影响因子：
3.2
通讯作者：
Davies, Gideon J.
中科院分区：
文献类型：
--
作者：
Males, Alexandra;Raich, Lluis;Davies, Gideon J.
糖苷水解酶（GH）具有不同的家族特异性构象，这为设计紧密结合的特异性酶抑制剂提供了诱人的前景。GH家族特异性抑制剂的一个主要实例，并且发现广泛的实际用途的一个实例是天然产物kifunensine，其是对GH家族47转化α-甘露聚糖酶具有选择性的低纳摩尔抑制剂。在这里，我们表明，通过量子力学方法，kifunensine被限制为“环翻转”的C-1（4）构象与另一个可访问的，但更高的能量，区域周围的B-1，B-4构象。与一系列GH47酶复合的基夫新的构象-包括本文报道的具有柄杆菌属CkGH 47和GH家族38和92 α-甘露聚糖酶的基夫新的原子级分辨率（1埃）结构-被映射到基夫新自由能景观上。这些研究表明，kifunensine能够模拟GH 47酶的产物状态，但无法模拟与其他家族甘露糖苷酶反应坐标相关的任何构象状态。
The varied yet family-specific conformational pathways used by individual glycoside hydrolases (GHs) offer a tantalising prospect for the design of tightly binding and specific enzyme inhibitors. A cardinal example of a GH-family-specific inhibitor, and one that finds widespread practical use, is the natural product kifunensine, which is a low-nanomolar inhibitor that is selective for GH family 47 inverting alpha-mannosidases. Here we show, through quantum-mechanical approaches, that kifunensine is restrained to a "ring-flipped" C-1(4) conformation with another accessible, but higher-energy, region around the B-1,B-4 conformation. The conformations of kifunensine in complex with a range of GH47 enzymes-including an atomic-level resolution (1 angstrom) structure of kifunensine with Caulobacter sp. CkGH47 reported herein and with GH family 38 and 92 alpha-mannosidases-were mapped onto the kifunensine free-energy landscape. These studies revealed that kifunensine has the ability to mimic the product state of GH47 enzymes but cannot mimic any conformational states relevant to the reaction coordinate of mannosidases from other families.