A molecular switch regulating transcriptional repression and activation of PPAR gamma
文献类型：期刊论文
| 作者 | Shang, Jinsai3; Mosure, Sarah A.3,4,5; Zheng, Jie3,6; Brust, Richard3; Bass, Jared3; Nichols, Ashley2; Solt, Laura A.1; Griffin, Patrick R.1,3; Kojetin, Douglas J.1,3 |
| 刊名 | NATURE COMMUNICATIONS
 |
| 出版日期 | 2020-02-19 |
| 卷号 | 11期号:1页码:14 |
| ISSN号 | 2041-1723 |
| DOI | 10.1038/s41467-020-14750-x |
| 通讯作者 | Kojetin, Douglas J.(dkojetin@scripps.edu) |
| 英文摘要 | Nuclear receptor (NR) transcription factors use a conserved activation function-2 (AF-2) helix 12 mechanism for agonist-induced coactivator interaction and NR transcriptional activation. In contrast, ligand-induced corepressor-dependent NR repression appears to occur through structurally diverse mechanisms. We report two crystal structures of peroxisome proliferator-activated receptor gamma (PPAR gamma) in an inverse agonist/corepressor-bound transcriptionally repressive conformation. Helix 12 is displaced from the solvent-exposed active conformation and occupies the orthosteric ligand-binding pocket enabled by a conformational change that doubles the pocket volume. Paramagnetic relaxation enhancement (PRE) NMR and chemical crosslinking mass spectrometry confirm the repressive helix 12 conformation. PRE NMR also defines the mechanism of action of the corepressor-selective inverse agonist T0070907, and reveals that apo-helix 12 exchanges between transcriptionally active and repressive conformations-supporting a fundamental hypothesis in the NR field that helix 12 exchanges between transcriptionally active and repressive conformations. Structural studies of nuclear receptor transcription factors revealed that nearly all nuclear receptors share a conserved helix 12 dependent transcriptional activation mechanism. Here the authors present two crystal structures of peroxisome proliferator-activated receptor gamma (PPAR gamma) in an inverse agonist/corepressor-bound transcriptionally repressive conformation, where helix 12 is located within the orthosteric ligand-binding pocket instead, and discuss mechanistic implications. |
| WOS关键词 | LIGAND-BINDING DOMAIN ; STRUCTURAL BASIS ; RECEPTOR-GAMMA ; DYNAMICS ; ANTAGONIST ; MECHANISM ; DETERMINANTS ; REVEALS ; AGONIST ; COMPLEX |
| 资助项目 | National Institutes of Health (NIH)[F32DK108442] ; National Institutes of Health (NIH)[R01DK105825] ; National Institutes of Health (NIH)[R01DK101871] ; Richard and Helen DeVos graduate fellowship award ; National Science Foundation (NSF) award[1359369] ; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences[DE-AC02-76SF00515] ; DOE Office of Biological and Environmental Research ; National Institutes of Health, National Institute of General Medical Sciences[P41GM103393] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| 出版者 | NATURE PUBLISHING GROUP |
| WOS记录号 | WOS:000558870300004 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/292311]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Kojetin, Douglas J. |
| 作者单位 | 1.Scripps Res Inst, Dept Mol Med, Jupiter, FL 33458 USA 2.Scripps Res Inst, Summer Undergrad Res Fellows SURF Program, Jupiter, FL 33458 USA 3.Scripps Res Inst, Dept Integrat Struct & Computat Biol, Jupiter, FL 33458 USA 4.Scripps Res Inst, Skaggs Grad Sch Chem & Biol Sci, Jupiter, FL 33458 USA 5.Scripps Res Inst, Dept Immunol & Microbiol, Jupiter, FL 33458 USA 6.Chinese Acad Sci, Shanghai Inst Mat Medica, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Shang, Jinsai,Mosure, Sarah A.,Zheng, Jie,et al. A molecular switch regulating transcriptional repression and activation of PPAR gamma[J]. NATURE COMMUNICATIONS,2020,11(1):14. |
| APA | Shang, Jinsai.,Mosure, Sarah A..,Zheng, Jie.,Brust, Richard.,Bass, Jared.,...&Kojetin, Douglas J..(2020).A molecular switch regulating transcriptional repression and activation of PPAR gamma.NATURE COMMUNICATIONS,11(1),14. |
| MLA | Shang, Jinsai,et al."A molecular switch regulating transcriptional repression and activation of PPAR gamma".NATURE COMMUNICATIONS 11.1(2020):14. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。