Molecular determinants of ER alpha and ER beta involved in selectivity of 16 alpha-iodo-7 beta estradiol.
The two known estrogen receptors, ER alpha and ER beta, are hormone inducible transcription factors that have distinct roles in regulating cell proliferation and differentiation. The natural ligand, 17 beta-estradiol (E2), binds with high affinity to both ER alpha and ER beta. However, a close analogue, 16 alpha-iodo-17 beta-estradiol (16 alpha IE2) showed about 10-fold selectivity for ER alpha over ER beta. From X-ray studies, it has been shown that the ligand-binding domains (LBD) of the two receptors are strikingly similar, and that only two changes fall within the binding cavity (ER alpha Leu384 to ER beta Met336, and ER alpha Met421 to ER beta Ile373). To understand the molecular basis for the ER alpha selectivity of 16 alpha IE2, mutants and chimeras of ER alpha and ER beta were generated, and ligand-binding and transactivation functions were studied. The ER alpha Leu384 Met mutant behaved like ER alpha WT in the presence of 16 alpha IE2; whereas the profile of the ER alpha Met421 Ile mutant was similar to that of ER beta WT. The ER beta mutant Ile373 Met behaved like ER alpha with 16 alpha IE2. The results clearly demonstrate the role of ER alpha Met421 in the ER alpha selectivity of 16 alpha IE2.
Bhat
Ramesh A
RA
Women's Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. bhatr@wyeth.com
Stauffer
Barbara
B
Unwalla
Rayomand J
RJ
Xu
Zhangbao
Z
Harris
Heather A
HA
Komm
Barry S
BS
D000595:Amino Acid Sequence; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D019295:Computational Biology; D017124:Conserved Sequence; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006801:Humans; D008024:Ligands; D008113:Liver Neoplasms / Q000473:pathology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008962:Models, Theoretical; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015533:Transcriptional Activation
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D004958:Estradiol; C024871:16 alpha-iodoestradiol; D008156:Luciferases