Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists
Abstract Neurokinin 3 receptor (NK3R) is a tachykinin receptor essential for the hypothalamic-pituitary-gonadal axis. The endogenous peptide agonist neurokinin B (NKB) preferentially activates NK3R, while substance P (SP) binds preferentially to NK1R. In addition, the SP analogue senktide more poten...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-06-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-023-00564-w |
| _version_ | 1827911024729128960 |
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| author | Wenjing Sun Fan Yang Huanhuan Zhang Qingning Yuan Shenglong Ling Yuanxia Wang Pei Lv Zelin Li Yifan Luo Dongsheng Liu Wanchao Yin Pan Shi H. Eric Xu Changlin Tian |
| author_facet | Wenjing Sun Fan Yang Huanhuan Zhang Qingning Yuan Shenglong Ling Yuanxia Wang Pei Lv Zelin Li Yifan Luo Dongsheng Liu Wanchao Yin Pan Shi H. Eric Xu Changlin Tian |
| author_sort | Wenjing Sun |
| collection | DOAJ |
| description | Abstract Neurokinin 3 receptor (NK3R) is a tachykinin receptor essential for the hypothalamic-pituitary-gonadal axis. The endogenous peptide agonist neurokinin B (NKB) preferentially activates NK3R, while substance P (SP) binds preferentially to NK1R. In addition, the SP analogue senktide more potently activates NK3R than NKB and SP. However, the mechanisms of preferential binding of peptide and NK3R activation remain elusive. Herein, we determined the cryogenic electron microscopy (cryo-EM) structures of the NK3R–Gq complex bound to NKB, SP and senktide. The three NK3R–Gq/peptide complexes utilize a class of noncanonical receptor activation mechanisms. Combining the structural analysis and functional assay illustrated that the consensus C-termini of the three peptide agonists share a conserved binding mode to NK3R, while the divergent N-termini of the peptides confer the preferential binding of the agonist to NK3R. In addition, the specific interactions between the N-terminus of senktide and the N-terminus and extracellular loops (ECL2 and ECL3) of NK3R lead to the improved activation displayed by senktide compared to SP and NKB. These findings pave the way to understand tachykinin receptor subtype selectivity and provide ideas to rationally develop drugs targeting NK3R. |
| first_indexed | 2024-03-13T01:57:31Z |
| format | Article |
| id | doaj.art-86a6848830a84a3ea55f00850efe8f39 |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-03-13T01:57:31Z |
| publishDate | 2023-06-01 |
| publisher | Nature Publishing Group |
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| series | Cell Discovery |
| spelling | doaj.art-86a6848830a84a3ea55f00850efe8f392023-07-02T11:06:55ZengNature Publishing GroupCell Discovery2056-59682023-06-019111210.1038/s41421-023-00564-wStructural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonistsWenjing Sun0Fan Yang1Huanhuan Zhang2Qingning Yuan3Shenglong Ling4Yuanxia Wang5Pei Lv6Zelin Li7Yifan Luo8Dongsheng Liu9Wanchao Yin10Pan Shi11H. Eric Xu12Changlin Tian13Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of ChinaDepartment of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of ChinaDepartment of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesDepartment of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of ChinaDepartment of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of ChinaDepartment of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of ChinaDepartment of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of ChinaDepartment of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of ChinaiHuman Institute, ShanghaiTech UniversityState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesDepartment of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of ChinaState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesDepartment of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, School of Life Sciences, Division of Life Sciences and Medicine, Joint Center for Biological Analytical Chemistry, Anhui Engineering Laboratory of Peptide Drug, Anhui Laboratory of Advanced Photonic Science and Technology, University of Science and Technology of ChinaAbstract Neurokinin 3 receptor (NK3R) is a tachykinin receptor essential for the hypothalamic-pituitary-gonadal axis. The endogenous peptide agonist neurokinin B (NKB) preferentially activates NK3R, while substance P (SP) binds preferentially to NK1R. In addition, the SP analogue senktide more potently activates NK3R than NKB and SP. However, the mechanisms of preferential binding of peptide and NK3R activation remain elusive. Herein, we determined the cryogenic electron microscopy (cryo-EM) structures of the NK3R–Gq complex bound to NKB, SP and senktide. The three NK3R–Gq/peptide complexes utilize a class of noncanonical receptor activation mechanisms. Combining the structural analysis and functional assay illustrated that the consensus C-termini of the three peptide agonists share a conserved binding mode to NK3R, while the divergent N-termini of the peptides confer the preferential binding of the agonist to NK3R. In addition, the specific interactions between the N-terminus of senktide and the N-terminus and extracellular loops (ECL2 and ECL3) of NK3R lead to the improved activation displayed by senktide compared to SP and NKB. These findings pave the way to understand tachykinin receptor subtype selectivity and provide ideas to rationally develop drugs targeting NK3R.https://doi.org/10.1038/s41421-023-00564-w |
| spellingShingle | Wenjing Sun Fan Yang Huanhuan Zhang Qingning Yuan Shenglong Ling Yuanxia Wang Pei Lv Zelin Li Yifan Luo Dongsheng Liu Wanchao Yin Pan Shi H. Eric Xu Changlin Tian Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists Cell Discovery |
| title | Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists |
| title_full | Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists |
| title_fullStr | Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists |
| title_full_unstemmed | Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists |
| title_short | Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists |
| title_sort | structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists |
| url | https://doi.org/10.1038/s41421-023-00564-w |
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