The Promiscuity of Allosteric Regulation of Nuclear Receptors by Retinoid X Receptor

Clark, Alexander K.; Wilder, J. Heath; Grayson, Aaron W.; Johnson, Quentin R.; Lindsay, Richard J.; Nellas, Ricky B.; Fernandez, Elias J.; Shen, Tongye

doi:10.1021/acs.jpcb.6b02057

Cited by 20 publications

(25 citation statements)

References 39 publications

(90 reference statements)

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“…In RXR heterodimers (e.g. VDR-RXR, RAR-RXR, CAR-RXR, LXR-RXR and TR-RXR), the presence of RXR agonist 9-cis retinoic acid results in altered transactivation by the cognate receptor [58][59][60][61]. Mechanisms underscoring the propagation of signal across NR dimer interfaces have been reported, providing explanations for related events such as coregulator recruitment to NR dimers.…”

Section: Interdomain Allostery In Nrsmentioning

confidence: 99%

Ligand-Induced Allosteric Effects Governing SR Signaling

Okafor¹,

Colucci²,

Ortlund³

2019

Nuclear Receptor Research

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Steroid receptors (SRs) are a class of ligand-regulated transcription factors that regulate gene expression in response to the binding of steroid hormones. Ligand binding drives conformational changes within the SR ligand binding domain that alters the receptors' affinity for coregulator proteins that in turn modulate chromatin state and either promote or block the recruitment of transcriptional machinery to a gene. Structural characterizations of SRs have provided insight into how these conformational rearrangements modulate receptor function, including signaling between the ligand binding pocket and the site of coregulator binding. Here, we review some of the proposed structural mechanisms put forward to explain the ability of ligands to modulate SR function. We also provide a discussion on computational methods that have contributed to the elucidation of SR allosteric regulation. Finally, we consider broader discussions of allostery within the SR family, such as receptor-induced reverse allostery and allosteric binding sites located outside of the canonical ligand interaction site.

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Section: Interdomain Allostery In Nrsmentioning

confidence: 99%

Ligand-Induced Allosteric Effects Governing SR Signaling

Okafor¹,

Colucci²,

Ortlund³

2019

Nuclear Receptor Research

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“…Two sets of molecular dynamics simulations of protein complexes were used in this study. The system setup details have been reported previously for E-PCA analysis ( 20 , 21 ) and are described in the Materials and Methods section. Here, we focused on conformations from a long-time simulation of the wild-type complex ( 23 ).…”

Section: Resultsmentioning

confidence: 99%

Characterizing the 3D structure and dynamics of chromosomes and proteins in a common contact matrix framework

Lindsay

Pham

Shen

et al. 2018

Nucleic Acids Research

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Conformational ensembles of biopolymers, whether proteins or chromosomes, can be described using contact matrices. Principal component analysis (PCA) on the contact data has been used to interrogate both protein and chromosome structures and/or dynamics. However, as these fields have developed separately, variants of PCA have emerged. Previously, a variant we hereby term Implicit-PCA (I-PCA) has been applied to chromosome contact matrices and revealed the spatial segregation of active and inactive chromatin. Separately, Explicit-PCA (E-PCA) has previously been applied to proteins and characterized their correlated structure fluctuations. Here, we swapped analysis methods (I-PCA and E-PCA), applying each to a different biopolymer type (chromosome or protein) than the one for which they were initially developed. We find that applying E-PCA to chromosome distance matrices derived from microscopy data can reveal the dominant motion (concerted fluctuation) of these chromosomes. Further, by applying E-PCA to Hi-C data across the human blood cell lineage, we isolated the aspects of chromosome structure that most strongly differentiate cell types. Conversely, when we applied I-PCA to simulation snapshots of proteins, the major component reported the consensus features of the structure, making this a promising approach for future analysis of semi-structured proteins.

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“…The chicken xenobiotic receptor (CXR) is closely related to PXR and CAR orthologs in mammals [25] and is capable of constitutively activating expression of THRSP. The ability of RXR to form homeodimers and heterodimers with several nuclear receptors has prompted the view that RXR acts as a 'promiscuous' regulator of nuclear receptors [26,27].…”

Section: Transcriptional Regulation Of Metabolism During the Fasting-mentioning

confidence: 99%

Transcriptome analyses of liver in newly-hatched chicks during the metabolic perturbation of fasting and re-feeding reveals THRSPA as the key lipogenic transcription factor

et al. 2020

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Background: The fasting-refeeding perturbation has been used extensively to reveal specific genes and metabolic pathways that control energy metabolism in the chicken. Most global transcriptional scans of the fasting-refeeding response in liver have focused on juvenile chickens that were 1, 2 or 4 weeks old. The present study was aimed at the immediate post-hatch period, in which newly-hatched chicks were subjected to fasting for 4, 24 or 48 h, then refed for 4, 24 or 48 h, and compared with a fully-fed control group at each age (D1-D4). Results: Visual analysis of hepatic gene expression profiles using hierarchical and K-means clustering showed two distinct patterns, genes with higher expression during fasting and depressed expression upon refeeding and those with an opposing pattern of expression, which exhibit very low expression during fasting and more abundant expression with refeeding. Differentially-expressed genes (DEGs), identified from five prominent pair-wise contrasts of fed, fasted and refed conditions, were subjected to Ingenuity Pathway Analysis. This enabled mapping of analysis-ready (AR)-DEGs to canonical and metabolic pathways controlled by distinct gene interaction networks. The largest number of hepatic DEGs was identified by two contrasts: D2FED48h/D2FAST48h (968 genes) and D2FAST48h/D3REFED24h (1198 genes). The major genes acutely depressed by fasting and elevated upon refeeding included ANGTPL, ATPCL, DIO2, FASN, ME1, SCD, PPARG, SREBP2 and THRSPA-a primary lipogenic transcription factor. In contrast, major lipolytic genes were up-regulated by fasting or down-regulated after refeeding, including ALDOB,

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The Promiscuity of Allosteric Regulation of Nuclear Receptors by Retinoid X Receptor

Cited by 20 publications

References 39 publications

Ligand-Induced Allosteric Effects Governing SR Signaling

Ligand-Induced Allosteric Effects Governing SR Signaling

Characterizing the 3D structure and dynamics of chromosomes and proteins in a common contact matrix framework

Transcriptome analyses of liver in newly-hatched chicks during the metabolic perturbation of fasting and re-feeding reveals THRSPA as the key lipogenic transcription factor

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