7tt8

From Proteopedia

Human LRH-1 LBD bound to agonist 6N-10CA and fragment of Tif2 coactivator

Structural highlights

7tt8 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.8Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NR5A2_HUMAN Binds to the sequence element 5'-AACGACCGACCTTGAG-3' of the enhancer II of hepatitis B virus genes, a critical cis-element of their expression and regulation. May be responsible for the liver-specific activity of enhancer II, probably in combination with other hepatocyte transcription factors. Key regulator of cholesterol 7-alpha-hydroxylase gene (CYP7A) expression in liver. May also contribute to the regulation of pancreas-specific genes and play important roles in embryonic development.

Publication Abstract from PubMed

Liver receptor homologue-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviating intestinal inflammation and metabolic dysregulation in the liver. LRH-1 contains a large ligand-binding pocket, but generating synthetic modulators has been challenging. We have had recent success generating potent and efficacious agonists through two distinct strategies. We targeted residues deep within the pocket to enhance compound binding and residues at the mouth of the pocket to mimic interactions made by phospholipids. Here, we unite these two designs into one molecule to synthesize the most potent LRH-1 agonist to date. Through a combination of global transcriptomic, biochemical, and structural studies, we show that selective modulation can be driven through contacting deep versus surface polar regions in the pocket. While deep pocket contacts convey high affinity, contacts with the pocket mouth dominate allostery and provide a phospholipid-like transcriptional response in cultured cells.

Differential Modulation of Nuclear Receptor LRH-1 through Targeting Buried and Surface Regions of the Binding Pocket.,Cato ML, Cornelison JL, Spurlin RM, Courouble VV, Patel AB, Flynn AR, Johnson AM, Okafor CD, Frank F, D'Agostino EH, Griffin PR, Jui NT, Ortlund EA J Med Chem. 2022 May 12;65(9):6888-6902. doi: 10.1021/acs.jmedchem.2c00235. Epub , 2022 May 3. PMID:35503419^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Cato ML, Cornelison JL, Spurlin RM, Courouble VV, Patel AB, Flynn AR, Johnson AM, Okafor CD, Frank F, D'Agostino EH, Griffin PR, Jui NT, Ortlund EA. Differential Modulation of Nuclear Receptor LRH-1 through Targeting Buried and Surface Regions of the Binding Pocket. J Med Chem. 2022 May 12;65(9):6888-6902. PMID:35503419 doi:10.1021/acs.jmedchem.2c00235