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KMID : 0620920210530010019
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Experimental & Molecular Medicine
2021 Volume.53 No. 1 p.19 ~ p.29
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Potent synthetic and endogenous ligands for the adopted orphan nuclear receptor Nurr1
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Jang Yong-Woo
Kim Woo-Ri
Leblanc Pierre
Kim Chun-Hyung
Kim Kwang-Soo
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Abstract
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Until recently, Nurr1 (NR4A2) was known as an orphan nuclear receptor without a canonical ligand-binding domain, featuring instead a narrow and tight cavity for small molecular ligands to bind. In-depth characterization of its ligand-binding pocket revealed that it is highly dynamic, with its structural conformation changing more than twice on the microsecond-to-millisecond timescale. This observation suggests the possibility that certain ligands are able to squeeze into this narrow space, inducing a conformational change to create an accessible cavity. The cocrystallographic structure of Nurr1 bound to endogenous ligands such as prostaglandin E1/A1 and 5,6-dihydroxyindole contributed to clarifying the crucial roles of Nurr1 and opening new avenues for therapeutic interventions for neurodegenerative and/or inflammatory diseases related to Nurr1. This review introduces novel endogenous and synthetic Nurr1 agonists and discusses their potential effects in Nurr1-related diseases.
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KEYWORD
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Drug discovery, Transcriptional regulatory elements
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