Identification of a second binding site in the estrogen receptor.
Fluorescence spectrometry data by Tyulmenkov and Klinge (Arch. Biochem. Biophys. 2000, 381, 135-142) suggest the presence of a second binding site in both subtypes ER alpha and ER beta of the estrogen receptor (ER). A cavity previously described as a solvent channel was located in close proximity to the steroid binding site of both ER subtypes. Derivatives of a tetrahydrochrysene (THC) compound, speculated in the literature to bind to a second binding site, were docked successfully in the second sites identified. However, computation of accurate interaction scores indicates preferred binding to the steroid binding site over the second binding site of both ER alpha and ER beta for all THC derivatives. Therefore, binding to this second site is probably not the reason the THC derivatives are agonists on ER alpha and antagonists on ER beta. Most likely, the smaller steroid binding site of ER beta compared to ER alpha and/or the apparent larger flexibility of helix 12 of ER beta make ER beta more readily adopt an antagonist conformation.
van Hoorn
Willem P
WP
Department of Molecular Informatics, Structure and Design, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom. willem_van_hoorn@sandwich.pfizer.com
D001665:Binding Sites; D002911:Chrysenes / Q000737:chemistry; D018360:Crystallography, X-Ray; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008958:Models, Molecular; D011960:Receptors, Estrogen / Q000737:chemistry*
D002911:Chrysenes; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen