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Full-length nuclear receptor allosteric regulation.

ABSTRACT: Nuclear receptors are a superfamily of transcription factors regulated by a wide range of lipids that include phospholipids, fatty acids, heme-based metabolites, and cholesterol-based steroids. Encoded as classic two-domain modular transcription factors, nuclear receptors possess a DNA-binding domain (DBD) and a lipid ligand-binding domain (LBD) containing a transcriptional activation function. Decades of structural studies on the isolated LBDs of nuclear receptors established that lipid-ligand binding allosterically regulates the conformation of the LBD, regulating transcriptional coregulator recruitment and thus nuclear receptor function. These structural studies have aided the development of several FDA-approved drugs, highlighting the importance of understanding the structure-function relationships between lipids and nuclear receptors. However, there are few published descriptions of full-length nuclear receptor structure and even fewer descriptions of how lipids might allosterically regulate full-length structure. Here, we examine multidomain interactions based on the published full-length nuclear receptor structures, evaluating the potential of interdomain interfaces within these nuclear receptors to act as inducible sites of allosteric regulation by lipids.

SUBMITTER: Choi WJ

PROVIDER: S-EPMC10388211 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Full-length nuclear receptor allosteric regulation.

Choi Woong Jae WJ Haratipour Zeinab Z Blind Raymond D RD

Journal of lipid research 20230624 8

Nuclear receptors are a superfamily of transcription factors regulated by a wide range of lipids that include phospholipids, fatty acids, heme-based metabolites, and cholesterol-based steroids. Encoded as classic two-domain modular transcription factors, nuclear receptors possess a DNA-binding domain (DBD) and a lipid ligand-binding domain (LBD) containing a transcriptional activation function. Decades of structural studies on the isolated LBDs of nuclear receptors established that lipid-ligand ...[more]

PMID: 37356665

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Project description:The nuclear receptor Liver Receptor Homolog-1 (LRH-1, NR5A2) is a ligand-regulated transcription factor and validated drug target for several human diseases. LRH-1 activation is regulated by small molecule ligands, which bind to the ligand binding domain (LBD) within the full-length LRH-1. We recently identified 57 compounds that bind LRH-1, and unexpectedly found these compounds regulated either the isolated LBD, or the full-length LRH-1 in cells, with little overlap. Here, we correlated compound binding energy from a single rigid-body scoring function with full-length LRH-1 activity in cells. Although docking scores of the 57 hit compounds did not correlate with LRH-1 regulation in wet lab assays, a subset of the compounds had large differences in binding energy docked to the isolated LBD vs. full-length LRH-1, which we used to empirically derive a new metric of the docking scores we call "ΔΔG". Initial regressions, correlations and contingency analyses all suggest compounds with high ΔΔG values more frequently regulated LRH-1 in wet lab assays. We then docked all 57 compounds to 18 separate crystal structures of LRH-1 to obtain averaged ΔΔG values for each compound, which robustly and reproducibly associated with full-length LRH-1 activity in cells. Network analyses on the 18 crystal structures of LRH-1 suggest unique communication paths exist between the subsets of LRH-1 crystal structures that produced high vs. low ΔΔG values, identifying a structural relationship between ΔΔG and the position of Helix 6, a previously established regulatory helix important for LRH-1 regulation. Together, these data suggest rigid-body computational docking can be used to quickly calculate ΔΔG, which positively correlated with the ability of these 57 hit compounds to regulate full-length LRH-1 in cell-based assays. We propose ΔΔG as a novel computational tool that can be applied to LRH-1 drug screens to prioritize compounds for resource-intense secondary screening.

Dataset Information

Full-length nuclear receptor allosteric regulation.

Publications

Full-length nuclear receptor allosteric regulation.

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