title: The conformational dynamics of H2-H3n and S2-H6 in gating ligand entry into the buried binding cavity of vitamin D receptor.
abstract: 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.
authors: Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors: Wei-Ven
authors: WV
authors: Tee
authors: Allergy and Immunology Research Centre, Institute for Medical Research, Jalan Pahang, 50588 Kuala Lumpur, Malaysia.
authors: Adiratna Mat
authors: AM
authors: Ripen
authors: Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia.|Centre of Research for Computational Sciences and Informatics in Biology, Bioindustry, Environment, Agriculture and Healthcare (CRYSTAL), University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors: Saharuddin Bin
authors: SB
authors: Mohamad
mesh_terms: D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011487:Protein Conformation; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D018167:Receptors, Calcitriol / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001059:Apoproteins; D008024:Ligands; D018167:Receptors, Calcitriol; C579457:VDR protein, human