7TT8

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

Summary for 7TT8

• Entry DOI: 10.2210/pdb7tt8/pdb
• Descriptor: Nuclear receptor subfamily 5 group A member 2, Nuclear receptor coactivator 2, 10-[(3aR,6S,6aR)-3-phenyl-3a-(1-phenylethenyl)-6-(sulfamoylamino)-1,3a,4,5,6,6a-hexahydropentalen-2-yl]decanoic acid (non-preferred name), ... (4 entities in total)
• Functional Keywords: lrh-1, nuclear receptor, ligand, synthetic agonist, nuclear protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 30661.45

Authors

Cato, M.L.,Ortlund, E.A. (deposition date: 2022-01-31, release date: 2022-05-11, Last modification date: 2023-10-18)

Primary citation

Cato, M.L.,Cornelison, J.L.,Spurlin, R.M.,Courouble, V.V.,Patel, A.B.,Flynn, A.R.,Johnson, A.M.,Okafor, C.D.,Frank, F.,D'Agostino, E.H.,Griffin, P.R.,Jui, N.T.,Ortlund, E.A.
Differential Modulation of Nuclear Receptor LRH-1 through Targeting Buried and Surface Regions of the Binding Pocket.
J.Med.Chem., 65:6888-6902, 2022

PubMed Abstract: 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.

PubMed: 35503419
DOI: 10.1021/acs.jmedchem.2c00235

Experimental method

X-RAY DIFFRACTION (2.8 Å)