Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)
文献类型：期刊论文
| 作者 | Chen, Yan13; Zhou, Qingtong13; Wang, Jiang10,11,12 ; Xu, Youwei9; Wang, Yun8; Yan, Jiahui1,7,9; Wang, Yibing12; Zhu, Qi8; Zhao, Fenghui7,9; Li, Chenghao10,12
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| 刊名 | NATURE COMMUNICATIONS
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| 出版日期 | 2023-01-30 |
| 卷号 | 14期号:1页码:492 |
| DOI | 10.1038/s41467-023-36182-z |
| 文献子类 | Article |
| 英文摘要 | Relaxin family peptide receptor 4 (RXFP4) regulates pleiotropic biological processes. Here, authors report cryo-EM structures revealing the ligand-binding modes and key determinants of peptidomimetic agonism and subtype selectivity Members of the insulin superfamily regulate pleiotropic biological processes through two types of target-specific but structurally conserved peptides, insulin/insulin-like growth factors and relaxin/insulin-like peptides. The latter bind to the human relaxin family peptide receptors (RXFPs). Here, we report three cryo-electron microscopy structures of RXFP4-G(i) protein complexes in the presence of the endogenous ligand insulin-like peptide 5 (INSL5) or one of the two small molecule agonists, compound 4 and DC591053. The B chain of INSL5 adopts a single alpha-helix that penetrates into the orthosteric pocket, while the A chain sits above the orthosteric pocket, revealing a peptide-binding mode previously unknown. Together with mutagenesis and functional analyses, the key determinants responsible for the peptidomimetic agonism and subtype selectivity were identified. Our findings not only provide insights into ligand recognition and subtype selectivity among class A G protein-coupled receptors, but also expand the knowledge of signaling mechanisms in the insulin superfamily. |
| WOS关键词 | LEUCINE-RICH REPEAT ; CRYSTAL-STRUCTURE ; ACTIVE STRUCTURE ; IN-VITRO ; INSULIN ; ACTIVATION ; IDENTIFICATION ; ANTAGONIST ; GPCR142 ; BUILDER |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000955780200001 |
| 出版者 | NATURE PORTFOLIO |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309716]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Yang, Dehua; Liu, Hong; Wang, Ming-Wei |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 2.Univ Tokyo, Sch Sci, Dept Chem, Tokyo 1130033, Japan 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China; 4.Univ Melbourne, Dept Biochem & Mol Biol, Parkville, Vic 3052, Australia; 5.Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3052, Australia; 6.Res Ctr Deepsea Bioresources, Sanya 572025, Hainan, Peoples R China; 7.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 8.Genova Biotech Changzhou Co Ltd, Changzhou 213125, Peoples R China; 9.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 10.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Chen, Yan,Zhou, Qingtong,Wang, Jiang,et al. Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)[J]. NATURE COMMUNICATIONS,2023,14(1):492. |
| APA | Chen, Yan.,Zhou, Qingtong.,Wang, Jiang.,Xu, Youwei.,Wang, Yun.,...&Wang, Ming-Wei.(2023).Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4).NATURE COMMUNICATIONS,14(1),492. |
| MLA | Chen, Yan,et al."Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)".NATURE COMMUNICATIONS 14.1(2023):492. |
入库方式： OAI收割
来源：上海药物研究所
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