the structural basis of gas-responsive transcription by the human nuclear hormone receptor rev-erbβ的结构性基础由人类核激素受体rev-erbβgas-responsive转录.pdfVIP

PLoS BIOLOGY The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERBb Keith I. Pardee1,2, Xiaohui Xu 1,2,3, Jeff Reinking 1,2,7¤a, Anja Schuetz4¤b, Aiping Dong4, Suya Liu5, Rongguang Zhang6, Jens Tiefenbach 1,2, Gilles Lajoie5, Alexander N. Plotnikov4¤b, Alexey Botchkarev4, Henry M. Krause 1,2*, Aled Edwards1,2,3,4* 1 Banting and Best Department of Medical Research, The Department of Molecular Genetics, University of Toronto, Toronto, Canada, 2 Terrence Donnelly Centre for Cellular Biomolecular Research, University of Toronto, Toronto, Canada, 3 Midwest Center for Structural Genomics, University of Toronto, Toronto, Canada, 4 Structural Genomics Consortium, University of Toronto, Toronto, Canada, 5 Department of Biochemistry, University of Western Ontario, London, Ontario, Canada, 6 Midwest Center for Structural Genomics, Argonne National Lab, Argonne, Illinois, United States of America, 7 Department of Biology, State University of New York at New Paltz, New Paltz, New York, United States of America Heme is a ligand for the human nuclear receptors (NR) REV-ERBa and REV-ERBb, which are transcriptional repressors that play important roles in circadian rhythm, lipid and glucose metabolism, and diseases such as diabetes, atherosclerosis, inflammation, and cancer. Here we show that transcription repression mediated by heme-bound REV- ERBs is reversed by the addition of nitric oxide (NO), and that the heme and NO effects are mediated by the C-terminal ˚ ligand-binding domain (LBD). A 1.9 A crystal structure of the REV-ERBb LBD, in complex with the oxidized Fe(III) form of heme, shows that heme binds in a prototypical NR ligand-