3D models of human ERα and ERβ complexed with coumestrol

• Coumestrol has four poses in ERα and ERβ.
• Coumestrol has the same low energy pose for ERα and ERβ.
• In this pose, coumestrol has similar contacts to both ERs as does E2.
• Coumstrol also has a second favored pose for ERα.

Coumestrol, a phytoestrogen found in alfalfa, clover, and beans, has nM affinity for both estrogen receptor-α [ERα] and ERβ. Recently, a novel activity of coumestrol was reported: coumestrol binding to human ERβ represses microglia-mediated inflammation, which is associated with various neurodegenerative diseases, such as multiple sclerosis. In contrast, estradiol binding to ERβ had little or no effect on repression of microglia-mediated inflammation. Coumestrol and estradiol have several structural differences, which suggest that each ligand could induce different conformations in ERβ and, thus, different transcriptional responses in brain microglia. To begin to understand how coumestrol binds to ERβ and ERα, we constructed 3D models of coumestrol with human ERβ and ERα, which were compared to the structures of these ERs with estradiol. Of four possible orientations of coumestrol in ERα and ERβ, one orientation had the most favorable contacts with both ERs. Other phytochemicals may activate ERβ and inhibit inflammation in brain microglia and be useful therapeutics for inflammatory conditions in the brain.

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