Comparative Structural Analysis of ERa and ERb Bound to Selective Estrogen Agonists and Antagonists
Abstract
The goal of this investigation is to determine the three-dimensional structures of the two known human estrogen receptors (ERalpha and ERBeta) complexed with receptor-selective estrogens and antiestrogens (SERMs). The crystallographic structures of ERalpha and ERbeta ligand binding domains complexed with cis- R,R-diethyl-tetrahydrochrysene-2, 8 -diol (R,R-THC) have been solved, suggesting mechanisms by which this compound can act as an ERalpha agonist and as an ERbeta antagonist. Although agonists and antagonists bind at the same site within the core of the ER LBD, each induces distinct conformations in the transactivation domain (AF-2) of the LBD, especially in the positioning of helix 12, providing structural evidence for multiple mechanisms of selective agonism and antagonism. Previously determined structures of ERalpha with 4-hydroxytamoxifen (0HT) and diethylstilbestrol (DES) collectively revealed and defined a multipurpose docking site on ERalpha and ERbeta that can accommodate either helix 12, in the presence of OHT, or one of several co-regulators in the presence of DES. Interestingly, R,R-THC antagonizes ERBeta in a manner very different from OHT and raloxifene) ,by filling the ligand binding pocket of ERbeta sub-optimally and acting as a passive antagonist, a novel concept. In contrast, R,R-THC is clearly able to induce the agonist-bound conformation of helix 12 when bound to ERalpha, by making most of the same contacts as DES or estradiol. It is anticipated that the utilization structure based ligand design will allow the creation of new compounds that act differently on the two ERs and possess novel therapeutic properties that can be exploited to prevent or treat breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2000
- Accession Number
- ADA385503
Entities
People
- Geoggrey Greene
Organizations
- University of Chicago