Jørgensen Anne Marie, Tagmose Lena, Jørgensen Anne Marie M, Bøgesø Klaus P, Peters Günther H
MEMPHYS-Center for Biomembrane Physics, Department of Chemistry, Technical University of Denmark, Building 206, 2800 Kgs. Lyngby, Denmark.
ChemMedChem. 2007 Jun;2(6):827-40. doi: 10.1002/cmdc.200600243.
We have performed molecular dynamics simulations of a homology model of the human serotonin transporter (hSERT) in a membrane environment and in complex with either the natural substrate 5-HT or the selective serotonin reuptake inhibitor escitalopram. We have also included a transporter homologue, the Aquifex aeolicus leucine transporter (LeuT), in our study to evaluate the applicability of a simple and computationally attractive membrane system. Fluctuations in LeuT extracted from simulations are in good agreement with crystallographic B factors. Furthermore, key interactions identified in the X-ray structure of LeuT are maintained throughout the simulations indicating that our simple membrane system is suitable for studying the transmembrane protein hSERT in complex with 5-HT or escitalopram. For these transporter complexes, only relatively small fluctuations are observed in the ligand-binding cleft. Specific interactions responsible for ligand recognition, are identified in the hSERT-5HT and hSERT-escitalopram complexes. Our findings are in good agreement with predictions from mutagenesis studies.
我们对人血清素转运体（hSERT）的同源模型在膜环境中以及与天然底物5-羟色胺（5-HT）或选择性血清素再摄取抑制剂依他普仑形成复合物的情况进行了分子动力学模拟。我们的研究中还纳入了一种转运体同源物，即嗜热栖热菌亮氨酸转运体（LeuT），以评估一种简单且计算上有吸引力的膜系统的适用性。从模拟中提取的LeuT的波动与晶体学B因子高度吻合。此外，在整个模拟过程中，LeuT的X射线结构中确定的关键相互作用得以维持，这表明我们的简单膜系统适用于研究与5-HT或依他普仑形成复合物的跨膜蛋白hSERT。对于这些转运体复合物，在配体结合裂隙中仅观察到相对较小的波动。在hSERT - 5HT和hSERT - 依他普仑复合物中确定了负责配体识别的特异性相互作用。我们的研究结果与诱变研究的预测高度一致。
