Tee Wei-Ven, Ripen Adiratna Mat, Mohamad Saharuddin Bin
Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Allergy and Immunology Research Centre, Institute for Medical Research, Jalan Pahang, 50588 Kuala Lumpur, Malaysia.
Sci Rep. 2016 Oct 27;6:35937. doi: 10.1038/srep35937.
Crystal structures of holo vitamin D receptor (VDR) revealed a canonical conformation in which the ligand is entrapped in a hydrophobic cavity buried in the ligand-binding domain (LBD). The mousetrap model postulates that helix 12 is positioned away from the domain to expose the interior cavity. However, the extended form of helix 12 is likely due to artifacts during crystallization. In this study, we set out to investigate conformational dynamics of apo VDR using molecular dynamics simulation on microsecond timescale. Here we show the neighboring backbones of helix 2-helix 3n and beta strand 2-helix 6 of LBD, instead of the helix 12, undergo large-scale motion, possibly gating the entrance of ligand to the ligand binding domain. Docking analysis to the simulated open structure of VDR with the estimated free energy of -37.0 kJ/mol, would emphasise the role of H2-H3n and S2-H6 in facilitating the entrance of calcitriol to the LBD of VDR.
全酶维生素D受体（VDR）的晶体结构揭示了一种典型构象，其中配体被困在埋于配体结合域（LBD）的疏水腔中。捕鼠器模型假定螺旋12远离该结构域以暴露内部腔室。然而，螺旋12的延伸形式可能是结晶过程中的假象。在本研究中，我们着手使用微秒时间尺度的分子动力学模拟来研究无配体VDR的构象动力学。在此我们表明，LBD的螺旋2 - 螺旋3n和β链2 - 螺旋6的相邻主链，而非螺旋12，经历了大规模运动，这可能控制着配体进入配体结合域的入口。对VDR模拟开放结构进行对接分析，估计自由能为 -37.0 kJ/mol，这将强调H2 - H3n和S2 - H6在促进骨化三醇进入VDR的LBD中的作用。
