The mechanism of the effect of U18666a on blocking the activity of 3β-hydroxysterol Δ-24-reductase (DHCR24): molecular dynamics simulation study and free energy analysis
The mechanism of the effect of U18666a on blocking the activity of 3β-hydroxysterol Δ-24-reductase (DHCR24): molecular dynamics simulation study and free energy analysis
复制标题
U18666a阻断3β-羟基甾醇Delta-24-还原酶（DHCR24）活性的作用机制：分子动力学模拟研究和自由能分析
DOI：
10.1007/s00894-016-2907-2
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发表时间：
2016-02-01
影响因子：
2.2
通讯作者：
Lu, Xiuli
中科院分区：
文献类型：
--
作者：
Quan, Xiaoping;Chen, Xiuqiang;Lu, Xiuli
DHCR24 encodes 3 beta-hydroxysterol-Delta(24)-reductase (DHCR24) catalyzing the cholesterol synthesis from desmosterol using the flavin adenine dinucleotide (FAD) as a co-factor. It is generally accepted that U18666a inhibits the reductase activity of DHCR24, but the detailed mechanism remains elusive. To explore the mechanism of the inhibitory effect of U18666a on DHCR24, we performed molecular dynamics (MD) simulations of two complexes including complexes of DHCR24-FAD-desmosterol enzymatic reactive components with and without the inhibitor U18666a. We found that the U18666a bound into the hydrophobic package near the FAD package of DHCR24. Furthermore, binding free energy of DHCR24 and desmosterol without U18666a is -54.86 kcal/mol, while the system with U18666a is -62.23 kcal/mol, suggesting that the affinity of the substrate desmosterol to DHCR24 was increased in response to the U18666a. In addition, U18666a interacts with FAD by newly forming three hydrogen bonds with Lys292, Lys367, and Gly438 of DHCR24. Finally, secondary structural analysis data obtained from the surrounding hot spots showed that U18666a induced dramatic secondary structural changes around the key residues in the interaction of DHCR24, FAD, and desmosterol. Taken together, these results for the first time demonstrate at the molecular structure level that U18666a blocks DHCR24 activity through an allosteric inhibiting mechanism, which may provide new insight into the development of a new type of cholesterol-lowering drug targeting to block the activity of DHCR24.
