Crystal structure of the Frizzled 4 receptor in a ligand-free state
文献类型：期刊论文
| 作者 | Yang, Shifan12; Wu, Yiran12; Xu, Ting-Hai1; de Waal, Parker W.1; He, Yuanzheng2; Pu, Mengchen12; Chen, Yuxiang3,4,5,12; DeBruine, Zachary J.1; Zhang, Bingjie12; Zaidi, Saheem A.6,7 |
| 刊名 | NATURE
 |
| 出版日期 | 2018-08-30 |
| 卷号 | 560期号:7720页码:666-+ |
| ISSN号 | 0028-0836 |
| DOI | 10.1038/s41586-018-0447-x |
| 文献子类 | Article |
| 英文摘要 | Frizzled receptors (FZDs) are class-F G-protein-coupled receptors (GPCRs) that function in Wnt signalling and are essential for developing and adult organisms(1,2). As central mediators in this complex signalling pathway, FZDs serve as gatekeeping proteins both for drug intervention and for the development of probes in basic and in therapeutic research. Here we present an atomic-resolution structure of the human Frizzled 4 receptor (FZD4) transmembrane domain in the absence of a bound ligand. The structure reveals an unusual transmembrane architecture in which helix VI is short and tightly packed, and is distinct from all other GPCR structures reported so far. Within this unique transmembrane fold is an extremely narrow and highly hydrophilic pocket that is not amenable to the binding of traditional GPCR ligands. We show that such a pocket is conserved across all FZDs, which may explain the long-standing difficulties in the development of ligands for these receptors. Molecular dynamics simulations on the microsecond timescale and mutational analysis uncovered two coupled, dynamic kinks located at helix VII that are involved in FZD4 activation. The stability of the structure in its ligand-free form, an unfavourable pocket for ligand binding and the two unusual kinks on helix VII suggest that FZDs may have evolved a novel ligand-recognition and activation mechanism that is distinct from that of other GPCRs. |
| WOS关键词 | MOLECULAR-DYNAMICS ; WNT PATHWAY ; PROTEINS ; DISEASE ; DIMERIZATION ; RECOGNITION ; MEMBRANES ; DATABASE ; SYSTEM ; TARGET |
| 资助项目 | National Natural Science Foundation (NSF) of China[31670736] ; National Key Research and Development Program of China[2018YFA0507004] ; National Key Research and Development Program of China[2016YCF0905902] ; NSF of Shanghai[16ZR1448500] ; Russian Foundation for Basic Research[RFBR 18-34-00990] ; Shanghai Municipal Government, ShanghaiTech University[00000000] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| 出版者 | NATURE PUBLISHING GROUP |
| WOS记录号 | WOS:000443218600054 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279609]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Xu, Fei |
| 作者单位 | 1.Van Andel Res Inst, Innovat & Integrat Program, Ctr Canc & Cell Biol, Grand Rapids, MI USA; 2.Harbin Inst Technol, Sch Life Sci & Technol, Ctr Life Sci, Harbin, Heilongjiang, Peoples R China; 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Shanghai, Peoples R China; 5.Univ Chinese Acad Sci, Beijing, Peoples R China; 6.Univ Southern Calif, Dept Biol Sci, Bridge Inst, Los Angeles, CA 90089 USA; 7.Univ Southern Calif, Dept Chem, Bridge Inst, Los Angeles, CA 90089 USA; 8.Moscow Inst Phys & Technol, Dolgoprudnyi, Russia; 9.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Struct & Funct Drug Targets, Shanghai, Peoples R China 10.Chinese Acad Sci, Shanghai Inst Mat Med, VARI SIMM Ctr, Key Lab Receptor Res, Shanghai, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Yang, Shifan,Wu, Yiran,Xu, Ting-Hai,et al. Crystal structure of the Frizzled 4 receptor in a ligand-free state[J]. NATURE,2018,560(7720):666-+. |
| APA | Yang, Shifan.,Wu, Yiran.,Xu, Ting-Hai.,de Waal, Parker W..,He, Yuanzheng.,...&Xu, Fei.(2018).Crystal structure of the Frizzled 4 receptor in a ligand-free state.NATURE,560(7720),666-+. |
| MLA | Yang, Shifan,et al."Crystal structure of the Frizzled 4 receptor in a ligand-free state".NATURE 560.7720(2018):666-+. |
入库方式： OAI收割
来源：上海药物研究所
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