Homology modelling of the nuclear receptors: human oestrogen receptorbeta (hERbeta), the human pregnane-X-receptor (PXR), the Ah receptor (AhR) and the constitutive androstane receptor (CAR) ligand binding domains from the human oestrogen receptor alpha (hERalpha) crystal structure, and the human peroxisome proliferator activated receptor alpha (PPARalpha) ligand binding domain from the human PPARgamma crystal structure.
We have generated by homology the three-dimensional structures of the ligand binding domain (LBD) of several interrelated human steroid hormone receptors (SHRs). These are the oestrogen receptor beta (hERbeta), the pregnane-X-receptor (PXR), the Ah receptor (AhR) and the constitutive androstane receptor (CAR). They were produced by homology modelling from the human oestrogen receptor alpha (hERalpha) crystallographic coordinates [Nature 389 (1997) 753] as a template together with the amino acid sequences for hERbeta [FEBS Lett. 392 (1996) 49], PXR [J. Clin. Invest. 102 (1998) 1016], AhR [Proc. Natl. Acad. Sci. U.S.A. 89 (1992) 815] and CAR [Nature 395 (1998) 612; Mol. Cell. Biol. 14 (1994) 1544], respectively. The selective endogenous ligand, in each case, was docked interactively within the putative ligand binding site using the position of oestradiol in hERalpha as a guide, and the total energy was calculated. In each receptor model a number of different ligands known to fit closely within the ligand binding site were interactively docked and binding interactions noted. Specific binding interactions included combinations of hydrogen bonding and hydrophobic contacts with key amino acid sidechains, which varied depending on the nature of the ligand and receptor concerned. We also produced the human peroxisome proliferator activated receptor alpha (PPARalpha) by homology modelling using the human PPARgamma (hPPARgamma) LBD crystallographic coordinates summarised in [Toxicol. In Vitro 12 (1998) 619] as a template together with the amino acid sequence for hPPARalpha [Toxicol. In Vitro 12 (1998) 619; Nature 395 (1998) 137]. The models will provide a useful tool in unravelling the complexity in the physiologic response to xenobiotics by examining the ligand binding interactions and differences between the steroid hormone receptors activation or inactivation by their ligands.
Jacobs
M N
MN
Molecular Toxicology Group, School of Biomedical and Life Sciences, University of Surrey, Guildford, UK. m.jacobs@surrey.ac.uk
Dickins
M
M
Lewis
D F V
DF
D000595:Amino Acid Sequence; D000090702:Constitutive Androstane Receptor; D018360:Crystallography, X-Ray; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006801:Humans; D008024:Ligands; D008953:Models, Anatomic; D008954:Models, Biological; D008958:Models, Molecular; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry*; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry*; D011960:Receptors, Estrogen / Q000737:chemistry*; D014157:Transcription Factors / Q000737:chemistry*
D000090702:Constitutive Androstane Receptor; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D014157:Transcription Factors