Abstract
Nuclear receptors (NRs) are a superfamily of transcription factors that regulate several processes such as metabolism, the cell cycle, inflammation, and hormone signaling. Their dysregulation contributes to many conditions such as metabolic syndrome and cancer; therefore, NRs are attractive therapeutic targets. Lipophilic ligands such as phospholipids bind to NRs within a hydrophobic binding pocket and alter NR activity through allostery. However, desorbing lipophilic NR ligands is energetically unfavorable and requires chaperoning by lipid transporter proteins (LTPs). Some LTP subfamilies, such as the fatty acid binding proteins (FABPs), exhibit tissue-specific expression and may promote ligand selectivity in NRs. For NRs steroidogenic factor -1 (SF-1) and liver receptor homolog-1 (LRH-1), ligand selectivity is challenging due to nearly identical ligand binding pockets. Here, we discuss strategies to improve NR-targeted therapies by leveraging lipid transport proteins (LTPs) for ligand delivery and improve ligand selectivity for the NR5A subgroup. Using high-throughput screening, we found that LTPs tend toward NR promiscuity. By integrating co-expression data, we suggest StarD14-HNF4α, FABP1-PXR, and FABP2-PXR are novel and potentially functional interactions. Structural and biophysical studies of LBP-3, a lifespan-extending C. elegans FABP, reveal that fatty acid binding relies on deep ionic interactions but resists many mutations to non-ionic residues within the binding cavity. Moreover, molecular simulations show that polyunsaturated fatty acid DGLA is flexible and thus adopts energetically favorable binding conformations explaining LPB-3’s preference for DGLA. We also humanized LRH-1 in mice to overcome challenges associated with testing LRH-1 agonism in vivo. Targeting LRH-1 in a humanized mouse model improves insulin sensitivity and reduces hepatic steatosis while balancing acute inflammatory signaling. Cross-reactivity with SF-1 remains a concern but SF-1—ligand structural data needed for robust structure activity relationship studies is lacking. To close this gap, we initiated development of a scaffold-protein platform to enable structure determination by cryogenic electron microscopy and provide new insights into NR5A ligand selectivity. Together, these findings offer new avenues for enhancing the precision and efficacy of NR-targeted therapies.
Table of Contents
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