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Hello. Welcome everyone to Chapter 3 of the nuclear receptors as therapeutic targets, HSTalk series and today we will talk about the structure of nuclear receptors.
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Here you see, in two different representations, the domain architecture of nuclear receptors on top in the actual tertiary structure and at the bottom, in a schematic representation. As you can see, the nuclear receptor starts with an N-terminal domain in blue that is typically unordered and also varies a lot in length and structure. It follows a DNA-binding domain abbreviated as DBD in yellow, which mediates the interaction with the DNA, followed by a hinge region in orange, and then the very important ligand binding domain, LBD, in red at the C terminus.
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These four different domains in the nuclear receptors, each fulfill different functions for the nuclear receptor or ligand-activated transcription factor activity. The N-terminal domain contains the so-called activation function 1 or AF1, which is ligand-independent and can, for example, respond to posttranslational modifications of the nuclear receptor and thereby modulate its activity. The N-terminal domain can interact with coregulators and it is typically highly disordered, but it is the main target of posttranslational modifications of nuclear receptors. It is not well conserved within the family, and therefore, varies a lot in length and structure, and it also contributes to the stability of nuclear receptors and may be involved in allosteric modulation of the receptor structure and activity. The DNA-binding domain in yellow is highly conserved within the family and highly structured through the two zinc fingers that it contains. It mediates the DNA binding and is also involved in dimerization of nuclear receptors but rather as a secondary player and has a weak contribution to the dimerization. It can also be a target of posttranslational modifications, and it has allosteric effects on other domains within the nuclear receptor. The hinge region is not very well conserved and typically disordered. It also varies in its length and just connects the DNA-binding domain with the ligand binding domain. In addition, it can contribute to dimerization, and very importantly, the hinge region typically contains the nuclear export signal or the nuclear localization signal, abbreviated as NLS, which mediates the translocation of the nuclear receptor into the nucleus. In addition, it can also be a target to posttranslational modifications and interact with coregulators. Then, in red, the very important domain for us that we are interested in nuclear receptors as therapeutic targets is the ligand binding domain which mediates the ligand binding. It contains the activation function 2, which is ligand-dependent, in contrast to the ligand-independent AF1 in the N-terminal domain. The ligand binding domain is overall well conserved within the family and highly structured. In addition to ligand binding, it also mediates the dimerization of nuclear receptors and the interaction with coregulators with contributions of the DNA-binding domain in the hinge region or virtually all the different domains but the ligand domain is key. It can also contain a nuclear localization signal and be a target of posttranslational modifications. Now let's have a look at all these domains, or the important domains, in more detail.

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