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Review
. 2012 Apr;33(2):271-99.
doi: 10.1210/er.2011-1033. Epub 2012 Mar 20.

Allosteric modulators of steroid hormone receptors: structural dynamics and gene regulation

Raj Kumar  1 , Iain J McEwan
Affiliations
Review

Allosteric modulators of steroid hormone receptors: structural dynamics and gene regulation

Raj Kumar et al. Endocr Rev. 2012 Apr.

Abstract

Steroid hormones are synthesized from cholesterol primarily in the adrenal gland and the gonads and play vital roles in normal physiology, the control of development, differentiation, metabolic homeostasis, and reproduction. The actions of these small lipophilic molecules are mediated by intracellular receptor proteins. It is just over 25 yr since the first cDNA for steroid receptors were cloned, a development that led to the birth of a superfamily of ligand-activated transcription factors: the nuclear receptors. The receptor proteins share structurally and functionally related ligand binding and DNA-binding domains but possess distinct N-terminal domains and hinge regions that are intrinsically disordered. Since the original cloning experiments, considerable progress has been made in our understanding of the structure, mechanisms of action, and biology of this important class of ligand-activated transcription factors. In recent years, there has been interest in the structural plasticity and function of the N-terminal domain of steroid hormone receptors and in the allosteric regulation of protein folding and function in response to hormone, DNA response element architecture, and coregulatory protein binding partners. The N-terminal domain can exist as an ensemble of conformers, having more or less structure, which prime this region of the receptor to rapidly respond to changes in the intracellular environment through hormone binding and posttranslation modifications. In this review, we address the question of receptor structure and function dynamics with particular emphasis on the structurally flexible N-terminal domain, intra- and interdomain communications, and the allosteric regulation of receptor action.

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Figures

Figure 1.
Figure 1.
General dynamics and mechanism of SHR action. SHR action is spatially, temporally, and structurally highly dynamic. In the absence of hormone, the receptor is complexed with co-chaperone molecules (green) in the cytoplasm. The NTD/AF1 exists in an ID conformation, compared with the well-ordered DBD and LBD. Factors affecting disorder-order transition of the SHR AF1/NTD are illustrated. The binding of hormone (I) causes rearrangement of regions in the LBD (helix 12, AF2), and this leads to translocation to the nucleus and binding to DNA response elements and coregulatory proteins (blue) (II). Under the influence of factors shown, NTD/AF1 undergoes disorder-order transition, resulting in the folding of NTD/AF1. In this conformation, AF1/NTD surfaces are well suited for the interaction with specific coactivators, binding of which further influences the conformation of NTD/AF1 and facilitates the assembly of the transcription initiation complex (blue) in a promoter-specific manner (III). The binding of DNA and/or coregulatory proteins may allosterically regulate ligand binding, which could lead to formation of SHR-transcription complexes (IV). The formation of transcriptionally competent complexes by the DNA-bound SHR (III) must be readily reversible, and the co-chaperone complex (green) may aid in dissociating the SHR-chromatin complex, recycling of the receptor protein to the cytoplasm, and stabilization of the ID NTD/AF1 (V). The SHR is also subject to posttranslational modifications, such as phosphorylation (P), which are likely to fine-tune the allosteric regulation of receptor structure and function.
Figure 2.
Figure 2.
SHR domain structure and function. A, Schematic representation of the domain organization of SHRs, showing the LBD and DBD and the structurally distinct NTD. Regions of the receptor protein important for ligand binding, DNA binding, dimerization, and transactivation are indicated below the protein. The position of the NLS and the CTE of the core DBD are also shown. Sites of potential posttranslational modification are indicated above the protein: including, acetylation (Ac), phosphorylation (P), methylation (Me) and sumoylation (SUMO-1; small ubiquitin-like modifier 1). B, Crystal structures for the LBD of the ERα bound with agonist (estradiol) (pdb 1ERE) or a selective ER modulator (4-hydroxhtamoxifen) (pdb 3ERT). The ligand binding pocket is indicated, as is the position of helices 1 and 12 and the AF2 surface (blue oval). C, Structures of the ERα-DBD (ER: pdb 1HCQ), which binds to a near palindromic DNA sequence as a homodimer. The presences of the P- and D-box amino acid residues are indicated. D, The crystal structure for PPARγ-RXRα heterodimer complex (pdp 3E00) on a direct repeat response element, with the half-sites separated by 1 bp. The PPARγ structure is in yellow, and RXR is in blue; the hinge region of PPAR is indicated.
Figure 3.
Figure 3.
ID proteins/domains exist as an ensemble of conformers, which collectively appear to be unstructured. Each conformer is in a reversible equilibrium with each other. Except for a very small fraction, which may be relatively well ordered (shown in center), all other conformers possess the characteristics of random coil or molten globule-like structures.
Figure 4.
Figure 4.
Folding of the SHR-NTD. The NTD exists has an ensemble of conformations, having more or less stable structure (middle molecule). A more stably folded conformation of the NTD can be induced or selected by small molecules (osmolytes), posttranslational modification (e.g., phosphorylation), DNA binding, and interactions with coregulatory proteins. In these models of NTD folding, the more stable structure is shown to be α-helical by the solid cylinders (blue).
Figure 5.
Figure 5.
Interdomain communication and allosteric regulator of SHRs. Various inter- and intramolecular events may allosterically regulate the structure and functions of the ID NTD/AF1 domain. Arrows indicate the flow of signals from one region/domain to another, throughout the SHR protein. For example, binding of different SRM in the ligand binding pocket can pass the signal to the surface of the LBD and dynamically reorient AF2 conformation and other parts of the domain. Signals are then passed to the hinge region, resulting in conformational rearrangements in the hinge, transferring to the DBD and eventually to ID NTD/AF1. In a similar fashion, HRE-DBD binding passes signals to influence the structure of NTD/AF1 and/or the AF2 surface. Direct binding of a coregulatory protein to NTD/AF1, site-specific phosphorylation, and possibly other posttranslational modifications, and even ID NTD/AF1 flanking sequences within the NTD can be avenues for allosteric coupling involving ID AF1 and other receptor domains.
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