8DAF

Human SF-1 LBD bound to synthetic agonist 6N-10CA and bacterial phospholipid

Summary for 8DAF

• Entry DOI: 10.2210/pdb8daf/pdb
• Descriptor: Steroidogenic factor 1, 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), ... (5 entities in total)
• Functional Keywords: sf-1, nuclear receptor, ligand, synthetic agonist, nuclear protein, steroidogenic factor-1, nr5a1
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 62140.51

Authors

D'Agostino, E.H.,Cato, M.L.,Ortlund, E.A. (deposition date: 2022-06-13, release date: 2023-06-28, Last modification date: 2023-10-25)

Primary citation

Cato, M.L.,D'Agostino, E.H.,Spurlin, R.M.,Flynn, A.R.,Cornelison, J.L.,Johnson, A.M.,Fujita, R.A.,Abraham, S.M.,Jui, N.T.,Ortlund, E.A.
Comparison of activity, structure, and dynamics of SF-1 and LRH-1 complexed with small molecule modulators.
J.Biol.Chem., 299:104921-104921, 2023

PubMed Abstract: Steroidogenic factor-1 (SF-1) is a phospholipid-sensing nuclear receptor expressed in the adrenal glands, gonads, and hypothalamus which controls steroidogenesis and metabolism. There is significant therapeutic interest in SF-1 because of its oncogenic properties in adrenocortical cancer. Synthetic modulators are attractive for targeting SF-1 for clinical and laboratory purposes due to the poor pharmaceutical properties of its native phospholipid ligands. While small molecule agonists targeting SF-1 have been synthesized, no crystal structures have been reported of SF-1 in complexes with synthetic compounds. This has prevented the establishment of structure-activity relationships that would enable better characterization of ligand-mediated activation and improvement in current chemical scaffolds. Here, we compare the effects of small molecules in SF-1 and its close homolog, liver receptor homolog-1 (LRH-1), and identify several molecules that specifically activate LRH-1. We also report the first crystal structure of SF-1 in complex with a synthetic agonist that displays low nanomolar affinity and potency for SF-1. We use this structure to explore the mechanistic basis for small molecule agonism of SF-1, especially compared to LRH-1, and uncover unique signaling pathways that drive LRH-1 specificity. Molecular dynamics simulations reveal differences in protein dynamics at the pocket mouth as well as ligand-mediated allosteric communication from this region to the coactivator binding interface. Our studies, therefore, shed important insight into the allostery driving SF-1 activity and show potential for modulation of LRH-1 over SF-1.

PubMed: 37328104
DOI: 10.1016/j.jbc.2023.104921

Experimental method

X-RAY DIFFRACTION (2.59 Å)