Fundamental to interpreting how ligands control a wide array of biological processes involving the estrogen receptor is the understanding of the linkage between small ligand/receptor and receptor co-regulator interactions. Structural data suggest that antagonist ligands mediate the estrogen receptor binding activity for regulatory proteins by modifying the conformation states of the receptor states of the receptor. For the first time, we show here that BIACORE, a surface plasmon resonance (SPR) optical biosensor, can be employed to monitor directly the dynamics of ligand/receptor complex formation and to characterize the functional states imposed by different ligands. These data demonstrate that agonist and antagonist ligands bind to estrogen receptor via distinct kinetic pathways Binding activity has also been shown to be a highly sensitive tool to characterize the binding of co-regulator proteins/peptides and hence to functionally define the conformational states imposed by the binding of small molecule ligands. A question which can now be addressed is: """"""""are there just two conformational/functional status, as suggested by structural data, or are there several, as might be implied from the biological data?"""""""" The ability to obtain high-resolution functional data on ligand/estrogen receptor interactions and regulatory protein binding permit us to answer this question and to expand our understanding of linkage between these two binding events. These linked functions are at the heart of the wide variety of biological and pharmaceutical responses that the estrogen receptor can elicit and provides the groundwork for a deeper understanding the behavior of nuclear hormone receptors in general.
| Rich, Rebecca L; Hoth, Lise R; Geoghegan, Kieran F et al. (2002) Kinetic analysis of estrogen receptor/ligand interactions. Proc Natl Acad Sci U S A 99:8562-7 |
