This work experimentally identifies the charge-transfer energy as a key factor governing the catalytic oxygen evolution reaction (OER) activity and mechanism across a wide range of perovskite chemistries.
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.
Article history:Received Revised Accepted Available online LRH-1 is a nuclear receptor that regulates lipid metabolism and homeostasis, making it an attractive target for the treatment of diabetes and non-alcoholic fatty liver disease. Building on recent structural information about ligand binding from our labs, we have designed a series of new LRH-1 agonists that further engage LRH-1 through added polar interactions. While the current synthetic approach to this scaffold has, in large part, allowed for decoration of the agonist core, significant variation of the bridgehead substituent is mechanistically precluded. We have developed a new synthetic approach to overcome this limitation, identified that bridgehead substitution is necessary for LRH-1 activation, and described an alternative class of bridgehead substituents for effective LRH-1 agonist development. We determined the crystal structure of LRH-1 bound to a bridgehead-modified compound, revealing a promising opportunity to target novel regions of the ligand-binding pocket to alter LRH-1 target gene expression..
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