title: A ligand-entry surface of the nuclear receptor superfamily consists of the helix H3 of the ligand-binding domain.
abstract: We successfully simulated receptor-ligand complex holo-form formation using the human retinoid X receptor-α ligand-binding domain (LBD) and its natural ligand, 9-cis retinoic acid. The success of this simulation was strongly dependent on the findings for an initial structure between the apo-LBD and the ligand as well as the discovery of the driving forces underlying the ligand-trapping and subsequent ligand-induction processes. Here, we would like to propose the "helix H3 three-point initial-binding hypothesis," which was instrumental in simulating the nuclear receptor (NR) superfamily. Using this hypothesis, we also succeeded in simulating holo-form formation of the human retinoic acid receptor-γ LBD and its natural ligand, all-trans retinoic acid. It is hoped that this hypothesis will facilitate novel understanding of both the ligand-trapping mechanism and the simultaneous C-terminal folding process in NR LBDs, as well as provide a new approach to drug design using a structure-based perspective.
authors.affiliation: Institute of Molecular Function, 2-105-14 Takasu, Misato-shi, Saitama 341-0037, Japan. Electronic address: motonori@molfunction.com.
authors.forename: Motonori
authors.initials: M
authors.lastname: Tsuji
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001059:Apoproteins / Q000737:chemistry; D030161:Avian Proteins / Q000737:chemistry; D001665:Binding Sites; D029721:Drosophila Proteins / Q000737:chemistry; D004331:Drosophila melanogaster; D015801:Helminth Proteins / Q000737:chemistry; D006801:Humans; D008024:Ligands; D051379:Mice; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry*; D013816:Thermodynamics; D014212:Tretinoin / Q000737:chemistry
chemical_list: D001059:Apoproteins; D030161:Avian Proteins; D029721:Drosophila Proteins; D015801:Helminth Proteins; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D014212:Tretinoin
keywords: AF-2 conformation; Driving force; Drug design; Holo-form formation; Inductive effect; Interaction energy; Ligand entry; Ligand-binding domain; Ligand-trapping mechanism; Nuclear receptor; Receptor surface