3PLZ

Human LRH1 LBD bound to GR470

Summary for 3PLZ

• Entry DOI: 10.2210/pdb3plz/pdb
• Related: 1YOK
• Descriptor: FTZ-F1 related protein, Nuclear receptor coactivator 2, (3aS,6aR)-5-[(4E)-oct-4-en-4-yl]-N,4-diphenyl-2,3,6,6a-tetrahydropentalen-3a(1H)-amine, ... (5 entities in total)
• Functional Keywords: alpha helical sandwhich, nuclear receptor, family five, transcription factor, co-activator, transcription-receptor-agonist complex, transcription/receptor/agonist
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : Q9UEC0 Q15596
• Total number of polymer chains: 4
• Total formula weight: 64028.31

Authors

Williams, S.P.,Xu, R.,Zuercher, W.J. (deposition date: 2010-11-15, release date: 2011-03-30, Last modification date: 2024-02-21)

Primary citation

Whitby, R.J.,Stec, J.,Blind, R.D.,Dixon, S.,Leesnitzer, L.M.,Orband-Miller, L.A.,Williams, S.P.,Willson, T.M.,Xu, R.,Zuercher, W.J.,Cai, F.,Ingraham, H.A.
Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2).
J.Med.Chem., 54:2266-2281, 2011

PubMed Abstract: The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-yl)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure-activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.

PubMed: 21391689
DOI: 10.1021/jm1014296

Experimental method

X-RAY DIFFRACTION (1.75 Å)