Liver receptor homolog-1: structures, related diseases, and drug discovery

Abstract

Liver receptor homolog-1 (LRH-1), a member of the nuclear receptor superfamily, is a ligand-regulated transcription factor that plays crucial roles in metabolism, development, and immunity. Despite being classified as an 'orphan' receptor due to the ongoing debate surrounding its endogenous ligands, recent researches have demonstrated that LRH-1 can be modulated by various synthetic ligands. This highlights the potential of LRH-1 as an attractive drug target for the treatment of inflammation, metabolic disorders, and cancer. In this review, we provide an overview of the structural basis, functional activities, associated diseases, and advancements in therapeutic ligand research targeting LRH-1.

Keywords: cancer; liver disease; liver receptor homolog 1; metabolic disorder; nuclear receptor; small molecule modulators.

Fig. 1. Domain organization and structure features of the ligand binding domain (LBD) of human LRH-1 (hLRH-1).

a Schematic diagram of the domain structure of NR5 subfamily members. LRH-1 and SF-1 display conserved modular domain architecture with an N-terminal domain lacking activation function 1 (AF-1), followed by a DNA binding domain (DBD) containing two extra structures named C-terminal extension (CTE) and Ftz-F1 helix, a hinge domain and an LBD with an activation function 2 (AF-2) domain. b Sequence alignment of the LBD of hLRH-1 and human SF-1 (hSF-1). A cartoon presentation of the overall architecture of hLRH-1 is depicted below the sequence alignment. Identical residues are labeled with an asterisk. Partially conserved residues are labeled with a colon. The residue numbering for hLRH-1 and hSF-1 are S300-A541 and N222-T461, respectively. Residues of hLRH-1 around the ligand are highlighted as red letters. Residues of hLRH-1 that are important for ligand binding are labeled on top of the sequences. c 3D architecture presentation of LRH-1 LBD domain (PDB: 6OQY). LRH-1 contains an additional layer formed by a rigid and relatively long helix H2 (yellow). H12 (green) packs against H3 (green) and H4 (green) to form the AF-2 surface where the co-activator (purple) binds. The agonist (cyan) is depicted as sticks. d Electrostatic potential mapped onto the LBD of hLRH-1 (PDB: 6OQY). Electrostatic map is generated via Pymol and display with gradient color. The agonist (cyan) is depicted as sticks.

Fig. 2. Regulation of LRH-1 transcriptional activity by co-regulators.

When LRH-1 recruits transcriptional co-activators, the complex binds to the SFRE of the target gene, activating the expression of downstream target genes. When LRH-1 recruits transcriptional co-repressors, the complex binds to the SFRE of the target gene, inhibiting the expression of downstream target genes.

Fig. 3. Diseases and pathologies related to LRH-1.

LRH-1 regulates the expression of multiple genes associated with cancers, metabolic disorders and inflammation.

Fig. 4. Co-crystal structures of small molecule modulators bound to hLRH-1 LBP.

a GSK8470 (PDB: 3PLZ, purple) forms a face-to-face π-π stack with His390. b RJW100 (PDB: 5L11, green) forms water-mediated hydrogen bonds with Asp389, His390, Arg393 and Thr352, and an edge-to-face π-π stack with His390. c 6N (PDB: 6OQY, light brown) forms direct hydrogen bonds with Met345 and Thr352, water-mediated hydrogen bonds with His390 and Arg393, and an edge-to-face π-π stack with His390. d 6N-10CA (PDB: 7TT8, pink) forms direct hydrogen bonds with Met345 and Thr352, water-mediated hydrogen bonds with His390 and Arg393, and an edge-to-face π-π stack with His390 deep within the pocket. Meanwhile, its carboxyl tail also forms direct or water-mediated hydrogen bonds with Gly421, Leu424, Tyr516 and Lys520.