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The activated ligand-regulated transcription factors collectively known as nuclear receptors respond to various lipid-soluble signals such as estrogen, progesterone, retinoic acid, oxysterols and thyroid hormone.
HREs, short DNA sequences typically located upstream of the transcription initiation site, are bound by nuclear hormone receptors in order to regulate gene transcription. These classical enhancer or silencer elements can influence mRNA synthesis regardless of their position and orientation within a gene's promoter region.
The targeting of receptors to their hormone response elements (HRE) is under the responsibility of the central DNA binding domain (DBD). The DBD, which embodies a type-II zinc finger motif, contains two subdomains that each comprises four cysteine residues coordinating a zinc ion and an alpha-helix. Operating as dimers, individual monomers from the DBD recognize six base pair sequences on DNA via half-sites where its reading helix enters into specific contacts with major grooves. This mechanism permits discrimination between various sequence orientations within aforementioned response element by taking note of spacing and orientation. Interestingly enough, these proteins still retain flexibility in recognizing different DNA sequences even when amino acid substitutions are present in their respective receptor's reading helices without disrupting binding entirely.
The correlation between the flexibility in DNA sequence recognition and specific base contacts observed in crystal structures can be ascertained. By conducting molecular dynamics studies on DNA binding of estrogen receptors with particular and non-specific sequences, we were able to find a solution for this query. For an elaborated understanding of our research study, kindly refer to the provided link.