Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)

Yan Chen, Qingtong Zhou, Jiang Wang, Youwei Xu, Yun Wang, Jiahui Yan, Yibing Wang, Qi Zhu, Fenghui Zhao, Chenghao Li, Chuan-Wei Chen, Xiaoqing Cai, Ross A .D. Bathgate, Chun Shen, H. Eric Xu, Dehua Yang (), Hong Liu () and Ming-Wei Wang ()
Additional contact information
Yan Chen: Fudan University
Qingtong Zhou: Fudan University
Jiang Wang: Chinese Academy of Sciences
Youwei Xu: Chinese Academy of Sciences
Yun Wang: Genova Biotech (Changzhou) Co., Ltd
Jiahui Yan: Chinese Academy of Sciences
Yibing Wang: Chinese Academy of Sciences
Qi Zhu: Genova Biotech (Changzhou) Co., Ltd
Fenghui Zhao: Chinese Academy of Sciences
Chenghao Li: Chinese Academy of Sciences
Chuan-Wei Chen: Research Center for Deepsea Bioresources
Xiaoqing Cai: Chinese Academy of Sciences
Ross A .D. Bathgate: University of Melbourne
Chun Shen: Genova Biotech (Changzhou) Co., Ltd
H. Eric Xu: Chinese Academy of Sciences
Dehua Yang: Chinese Academy of Sciences
Hong Liu: Chinese Academy of Sciences
Ming-Wei Wang: Fudan University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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–Gi 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 α-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.

Date: 2023
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DOI: 10.1038/s41467-023-36182-z

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