The Crystal Structure of the Orphan Nuclear Receptor NR2E3/PNR Ligand Binding Domain Reveals a Dimeric Auto-Repressed Conformation
文献类型：期刊论文
| 作者 | Tan, M. H. Eileen1,4; Zhou, X. Edward4; Soon, Fen-Fen1,4; Li, Xiaodan2,4; Li, Jun1 ; Yong, Eu-Leong1; Melcher, Karsten4; Xu, H. Eric3,4
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| 刊名 | PLOS ONE
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| 出版日期 | 2013-09-12 |
| 卷号 | 8期号:9 |
| ISSN号 | 1932-6203 |
| DOI | 10.1371/journal.pone.0074359 |
| 文献子类 | Article |
| 英文摘要 | Photoreceptor-specific nuclear receptor (PNR, NR2E3) is a key transcriptional regulator of human photoreceptor differentiation and maintenance. Mutations in the NR2E3-encoding gene cause various retinal degenerations, including Enhanced S-cone syndrome, retinitis pigmentosa, and Goldman-Favre disease. Although physiological ligands have not been identified, it is believed that binding of small molecule agonists, receptor desumoylation, and receptor heterodimerization may switch NR2E3 from a transcriptional repressor to an activator. While these features make NR2E3 a potential therapeutic target for the treatment of retinal diseases, there has been a clear lack of structural information for the receptor. Here, we report the crystal structure of the apo NR2E3 ligand binding domain (LBD) at 2.8 angstrom resolution. Apo NR2E3 functions as transcriptional repressor in cells and the structure of its LBD is in a dimeric auto-repressed conformation. In this conformation, the putative ligand binding pocket is filled with bulky hydrophobic residues and the activation-function-2 (AF2) helix occupies the canonical cofactor binding site. Mutations designed to disrupt either the AF2/cofactor-binding site interface or the dimer interface compromised the transcriptional repressor activity of this receptor. Together, these results reveal several conserved structural features shared by related orphan nuclear receptors, suggest that most disease-causing mutations affect the receptor's structural integrity, and allowed us to model a putative active conformation that can accommodate small ligands in its pocket. |
| WOS关键词 | S-CONE-SYNDROME ; PROTEIN-COUPLED-RECEPTOR ; DOMINANT RETINITIS-PIGMENTOSA ; ROD PHOTORECEPTOR DEVELOPMENT ; GOLDMANN-FAVRE-SYNDROME ; RETINAL DEGENERATION ; TRANSCRIPTIONAL REGULATION ; COMPOUND HETEROZYGOSITY ; MOLECULAR RECOGNITION ; AFFINITY TAGS |
| 资助项目 | Jay and Betty Van Andel Foundation[00000000] ; Amway (China) Limited[00000000] ; National Institutes of Health[5R01DK071662-08] ; National Research Foundation Singapore[NMRC/CSA/026/2011] ; NUS Graduate School for Integrative Sciences Engineering[00000000] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| 出版者 | PUBLIC LIBRARY SCIENCE |
| WOS记录号 | WOS:000326240100102 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277463]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Melcher, Karsten |
| 作者单位 | 1.Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Obstet & Gynecol, Natl Univ Hosp, Singapore 117595, Singapore; 2.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Key Lab Regenerat Biol, Guangzhou 510530, Guangdong, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Van Andel Res Inst,Shanghai Inst Mat Med Ctr, Shanghai 200031, Peoples R China 4.Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI USA; |
| 推荐引用方式 GB/T 7714 | Tan, M. H. Eileen,Zhou, X. Edward,Soon, Fen-Fen,et al. The Crystal Structure of the Orphan Nuclear Receptor NR2E3/PNR Ligand Binding Domain Reveals a Dimeric Auto-Repressed Conformation[J]. PLOS ONE,2013,8(9). |
| APA | Tan, M. H. Eileen.,Zhou, X. Edward.,Soon, Fen-Fen.,Li, Xiaodan.,Li, Jun.,...&Xu, H. Eric.(2013).The Crystal Structure of the Orphan Nuclear Receptor NR2E3/PNR Ligand Binding Domain Reveals a Dimeric Auto-Repressed Conformation.PLOS ONE,8(9). |
| MLA | Tan, M. H. Eileen,et al."The Crystal Structure of the Orphan Nuclear Receptor NR2E3/PNR Ligand Binding Domain Reveals a Dimeric Auto-Repressed Conformation".PLOS ONE 8.9(2013). |
入库方式： OAI收割
来源：上海药物研究所
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