Spontaneous Ligand Access Events to Membrane-Bound Cytochrome P450 2D6 Sampled at Atomic Resolution
Spontaneous Ligand Access Events to Membrane-Bound Cytochrome P450 2D6 Sampled at Atomic Resolution
复制标题
DOI：
10.1038/s41598-019-52681-w
复制
发表时间：
2019-11-11
影响因子：
4.6
通讯作者：
Smiesko, Martin
中科院分区：
文献类型：
--
作者：
Fischer, Andre;Smiesko, Martin
膜锚定酶细胞色素P450 2D 6（CYP 2D 6）参与了约25%的市售药物的代谢，其代谢性能显示出较高的个体间差异。虽然有人建议，配体从膜进入酶的埋藏活性位点，但没有证据表明无偏模拟支持这一假设。实验室实验未能捕获的访问过程，这是怀疑影响结合动力学。在这里，我们应用无偏分子动力学（MD）模拟来研究野生型CYP 2D 6的配体以及等位基因变体CYP 2D 6 *53的接近。在多个模拟中，底物从蛋白质-膜界面进入酶的活性位点，最终采用允许代谢反应的构象。我们提出了配体进入的必要步骤，结果表明，CYP 2D 6 *53代谢活性的增加可能是由促进配体摄取引起的。
The membrane-anchored enzyme Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of around 25% of marketed drugs and its metabolic performance shows a high interindividual variation. While it was suggested that ligands access the buried active site of the enzyme from the membrane, no proof from unbiased simulations has been provided to support this hypothesis. Laboratory experiments fail to capture the access process which is suspected to influence binding kinetics. Here, we applied unbiased molecular dynamics (MD) simulations to investigate the access of ligands to wild-type CYP2D6, as well as the allelic variant CYP2D6*53. In multiple simulations, substrates accessed the active site of the enzyme from the protein-membrane interface to ultimately adopt a conformation that would allow a metabolic reaction. We propose the necessary steps for ligand access and the results suggest that the increased metabolic activity of CYP2D6*53 might be caused by a facilitated ligand uptake.