期刊
JOURNAL OF LIPID RESEARCH
卷 64, 期 8, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.jlr.2023.100406
关键词
Full-length nuclear receptor; lipid structural biology; lipid regulation of full-length nuclear receptor; structural interfaces; lipid regulation of transcription
Nuclear receptors, regulated by various lipids, are transcription factors that possess a DNA-binding domain and a lipid ligand-binding domain. Structural studies on the isolated lipid ligand-binding domain have shown that lipid-ligand binding regulates the conformation of the domain and affects nuclear receptor function. Understanding the structure-function relationships between lipids and nuclear receptors is important for drug development. However, few studies have described the full-length structure of nuclear receptors and how lipids may allosterically regulate it.
Nuclear receptors are a superfamily of transcription factors regulated by a wide range of lipids that include phospholipids, fatty acids, heme-based metabolites, and cholesterol-based steroids. Encoded as classic two-domain modular transcription factors, nuclear receptors possess a DNA-binding domain (DBD) and a lipid ligand-binding domain (LBD) containing a transcriptional activation func-tion. Decades of structural studies on the isolated LBDs of nuclear receptors established that lipid-ligand binding allosterically regulates the conformation of the LBD, regulating transcriptional coregulator recruitment and thus nuclear receptor function. These structural studies have aided the development of several FDA-approved drugs, high-lighting the importance of understanding the structure-function relationships between lipids and nuclear receptors. However, there are few published descriptions of full-length nuclear receptor structure and even fewer descriptions of how lipids might allosterically regulate full-length structure. Here, we examine multidomain interactions based on the published full-length nuclear receptor structures, evaluating the potential of interdomain interfaces within these nuclear receptors to act as inducible sites of allosteric regulation by lipids.
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