Sandbox Reserved 490: Difference between revisions
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There are two types of estrogen receptors: estrogen receptor-α and estrogen receptor-β. There has been much research done on both ER-α and ER-β, and it is still unclear exactly how each functions. However, like all NRPs, the ER proteins have a highly conserved DNA-binding domain, a specific ligand-binding domain, and a highly variable N-terminus region. In ER proteins, the ligand-binding domain is located near the C-terminal region of the protein. Once bound, the mechanism of transcriptional regulation is dependent upon what co-factors and other signalling molecules are present in the cell.<ref>PMID:11581496</ref> | There are two types of estrogen receptors: estrogen receptor-α and estrogen receptor-β. There has been much research done on both ER-α and ER-β, and it is still unclear exactly how each functions. However, like all NRPs, the ER proteins have a highly conserved DNA-binding domain, a specific ligand-binding domain, and a highly variable N-terminus region. In ER proteins, the ligand-binding domain is located near the C-terminal region of the protein. Once bound, the mechanism of transcriptional regulation is dependent upon what co-factors and other signalling molecules are present in the cell.<ref>PMID:11581496</ref> | ||
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The ligand-bound estrogen receptor is also a <scene name='Sandbox_Reserved_490/Lbd_dimers/1'>dimer</scene>. Each unit has 12 <scene name='Sandbox_Reserved_490/Lbd_secondary_structure/1'>alpha helices and one antiparallel beta sheet</scene>. The <scene name='Sandbox_Reserved_490/Lbd_hydropobic_polar/1'>hydrophobic</scene> faces of the helices participating in the dimerization process face each other. | The ligand-bound estrogen receptor is also a <scene name='Sandbox_Reserved_490/Lbd_dimers/1'>dimer</scene>. Each unit has 12 <scene name='Sandbox_Reserved_490/Lbd_secondary_structure/1'>alpha helices and one antiparallel beta sheet</scene>. The <scene name='Sandbox_Reserved_490/Lbd_hydropobic_polar/1'>hydrophobic</scene> faces of the helices participating in the dimerization process face each other. | ||
The ligand-binding domain of each unit involves <scene name='Sandbox_Reserved_490/Lbd_active_residues/1'>key residues</scene> from helices 7, 8, and 9 in the binding pocket. Most of the residues are hydrophobic, to interact with the hydrophobic portions of the estrogen steroid. The Glu-353 and His-524 hydrogen bond directly with the hydroxyl groups on the estrogen ligand. | The ligand-binding domain of each unit involves <scene name='Sandbox_Reserved_490/Lbd_active_residues/1'>key residues</scene> from helices 7, 8, and 9 in the binding pocket. Most of the residues are hydrophobic, to interact with the hydrophobic portions of the estrogen steroid. The Glu-353 and His-524 hydrogen bond directly with the hydroxyl groups on the estrogen ligand (see image). | ||
The ligand used to determine this structure was estradiol, which is the physiologically appropriate ligand. Estradiol, or estrogen, has the following structure: | The ligand used to determine this structure was estradiol, which is the physiologically appropriate ligand. Estradiol, or estrogen, has the following structure: | ||
[[Image: | [[Image:Estradiol.gif]] | ||
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the occurrence of estrogen binding to ER may induce a rapid physiological change. However, it is unknown if this happens at the plasma membrane, withing the cytoplasm, or through the action of an unknown intermediary protein. | the occurrence of estrogen binding to ER may induce a rapid physiological change. However, it is unknown if this happens at the plasma membrane, withing the cytoplasm, or through the action of an unknown intermediary protein. | ||
The following image summarizes the | The following image summarizes the ligand-dependent genomic mechanism of ER, which is the most well known mechanism: | ||
[[Image:NRPaction.png]] | [[Image:NRPaction.png]] | ||
== Clinical Applications == | == Clinical Applications<ref>PMID:16511588</ref>== | ||
Estrogen and estrogen receptor proteins are known to have a wide variety of functions in multiple different tissue types. It is commonly known that estrogen acts as a morphogen, turning on genes that regulate sex differentiation and development. However, estrogen also plays an important role in other systems, such as the skeletal and cardiovascular systems. The specific genes that are turned on or off by estrogen in each cell type are influenced by what other compounds are in the cell. For example, the array of molecules in cardiovascular tissue is different from that of skeletal tissue, and thus the action of the estrogen-bound ER proteins are tissue-specific. | |||
The function of estrogen receptors has played a key role in the development of treatment strategies for many diseases, most notably for breast cancer. The suppression of ER activity in cancerous breast tissue, particularly ER-α, has been an effective hormonal treatment of breast cancer for decades. Other cancers that are strongly correlated with estrogen and ER activity are ovarian cancer, colon cancer, prostate cancer, and endometrial cancer. Increased ER activity in the skeletal system has been an effective treatment for osteoporosis. The symptoms of neurodegenerative diseases such as stroke, Parkinson's, and Alzheimer's, and cardiovascular diseases have been shown to be alleviated by estrogen and increased estrogen receptor activity. | |||
Further research on the mechanism of estrogen receptor action is necessary to improve upon treatment methods. Understanding the recruitment of specific cofactors in different tissues, the importance of the ERα:ERβ ratio, and how the combination of these things can change a compound's ER antagonist and agonist action will perhaps enable use to treat diseases more specifically and with a smaller incidence of negative side effects. | |||
== References == | == References == | ||
<references /> | <references /> | ||
