Full-length nuclear receptor allosteric regulation

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.

Automated summary

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.