title: Molecular dynamics simulations of human LRH-1: the impact of ligand binding in a constitutively active nuclear receptor.
abstract: The liver receptor homologue 1 (LRH-1 (NR5A2)) belongs to the orphan nuclear receptor family, indicating that initially no ligand was known. Although recent studies have shown that ligand binding can be obtained, the biological relevance remains elusive. Here, we modify the observed X-ray ligand into a biologically more significant phospholipid (phosphatidylserine, PS) present in human, to study, by molecular dynamics (MD) simulations, the impact of the ligand on the receptor and the interaction with different cofactor peptides. Furthermore, we characterize the interactions between receptor and the cofactor peptides of DAX-1 (NR0B1), Prox1 and SHP LXXLL box 1 and 2 (NR0B2) in terms of specificity. Our MD simulation results show different interaction patterns for the SHP box2 compared to DAX-1, PROX1 and SHP box1. SHP box2 shows specific interactions at its more C-terminal end while the other investigated peptides show specific interactions at several positions but particularly at the +2 site. The peptide +2 side chain interacts with a charged amino acid of the receptor, in hLRH-1 Asp372. Together with the charge clamp residues Arg361 and Glu534, Asp372 forms a triangle shaped charge clamp responsible for peptide orientation and increased affinity. The binding of the PS ligand causes no overall structural changes of the receptor but affects the interactions with cofactor peptides. The cofactor peptides from SHP decrease its interaction with the receptor upon ligand binding while DAX-1 and PROX1 are unchanged or increase. The diverse ligand binding response of the cofactor provides an opportunity for drug design with the possibility to create agonist ligands to modify cofactor interaction.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, SE-141 57 Huddinge, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Burendahl
authors.forename: Eckardt
authors.initials: E
authors.lastname: Treuter
authors.forename: Lennart
authors.initials: L
authors.lastname: Nilsson
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D005227:Fatty Acids; D008024:Ligands; C082631:NR5A2 protein, human; D010455:Peptides; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors