The first crystal structure of a DNA-free nuclear receptor DNA binding domain sheds light on DNA-driven allostery in the glucocorticoid receptor

• Type of Material: Article
• Authors: Filipp Frank, Emory University; C. Denise Okafor, Emory University; Eric Ortlund, Emory University
• Language: English
• Date: 2018-09-10
• Publisher: Nature Research (part of Springer Nature): Fully open access journals
• Publication Version: Final Published Version
• Copyright Statement: © 2018, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-018-31812-9
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 8
• Issue: 1
• Start Page: 13497
• End Page: 13497
• Grant/Funding Information: Use of the Advanced Photon Source was supported by the United States Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract W-31–109-Eng-38.; This work was supported by a W.M. Keck Foundation Medical Research Grant. C.D.O. is funded by an NIH-NIGMS Institutional Research and Career Development Award [Grant K12 GM000680].; Crystallographic data were collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory.
• Keywords: ACTIVATION; REPRESSION; SET; MOLECULAR-DYNAMICS; Science & Technology; SYSTEM; Science & Technology - Other Topics; Multidisciplinary Sciences; ELEMENT
• Research Categories: Chemistry, Biochemistry

Abstract

The glucocorticoid receptor (GR) is a steroid hormone receptor of the nuclear receptor family that regulates gene expression in response to glucocorticoid hormone signaling. Interaction with specific GR DNA binding sequences causes conformational changes in the GR DNA binding domain (DBD) that result in recruitment of specific sets of co-regulators that determine transcriptional outcomes. We have solved the crystal structure of GR DBD in its DNA-free state, the first such crystal structure from any nuclear receptor. In contrast to previous NMR structures, this crystal structure reveals that free GR DBD adopts a conformation very similar to DNA-bound states. The lever arm region is the most variable element in the free GR DBD. Molecular dynamics of the free GR DBD as well as GR DBD bound to activating and repressive DNA elements confirm lever arm flexibility in all functional states. Cluster analysis of lever arm conformations during simulations shows that DNA binding and dimerization cause a reduction in the number of conformations sampled by the lever arm. These results reveal that DNA binding and dimerization drive conformational selection in the GR DBD lever arm region and show how DNA allosterically controls GR structure and dynamics.