Department of Biochemistry and Synthetic Metabolism, Max Planck Institute for Terrestrial Microbiology, Marburg, Germany.
Microbial Protein Structure Group, Max Planck Institute for Terrestrial Microbiology, Marburg, Germany.
FEBS Lett. 2019 Mar;593(5):543-553. doi: 10.1002/1873-3468.13331. Epub 2019 Feb 22.
3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) catalyses the last step in mevalonate biosynthesis. HMGR is the target of statin inhibitors that regulate cholesterol concentration in human blood. Here, we report the properties and structures of HMGR from an archaeon Methanothermococcus thermolithotrophicus (mHMGR). The structures of the apoenzyme and the NADPH complex are highly similar to those of human HMGR. A notable exception is C-terminal helix (Lα10-11) that is straight in both mHMGR structures. This helix is kinked and closes the active site in the human enzyme ternary complex, pointing to a substrate-induced structural rearrangement of C-terminal in class-I HMGRs during the catalytic cycle.
3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGR）催化甲羟戊酸生物合成的最后一步。HMGR 是他汀类抑制剂的靶标，他汀类抑制剂调节人血液中的胆固醇浓度。在这里，我们报告了产甲烷菌 Methanothermococcus thermolithotrophicus（mHMGR）中 HMGR 的性质和结构。apo 酶和 NADPH 复合物的结构与人类 HMGR 的结构非常相似。一个值得注意的例外是 C 端螺旋（Lα10-11），它在两种 mHMGR 结构中都是直的。该螺旋发生扭曲，在人源酶三元复合物中关闭活性位点，这表明在催化循环中，I 类 HMGR 中的 C 端在底物诱导下发生结构重排。
