Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor
Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that exerts crucial metabolic functions by binding and activating its cognate receptor, GIPR. As an important therapeutic target, GIPR has been subjected to intensive structural studies without success. Here, we report the cryo-...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/68719 |
| _version_ | 1811201296931225600 |
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| author | Fenghui Zhao Chao Zhang Qingtong Zhou Kaini Hang Xinyu Zou Yan Chen Fan Wu Qidi Rao Antao Dai Wanchao Yin Dan-Dan Shen Yan Zhang Tian Xia Raymond C Stevens H Eric Xu Dehua Yang Lihua Zhao Ming-Wei Wang |
| author_facet | Fenghui Zhao Chao Zhang Qingtong Zhou Kaini Hang Xinyu Zou Yan Chen Fan Wu Qidi Rao Antao Dai Wanchao Yin Dan-Dan Shen Yan Zhang Tian Xia Raymond C Stevens H Eric Xu Dehua Yang Lihua Zhao Ming-Wei Wang |
| author_sort | Fenghui Zhao |
| collection | DOAJ |
| description | Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that exerts crucial metabolic functions by binding and activating its cognate receptor, GIPR. As an important therapeutic target, GIPR has been subjected to intensive structural studies without success. Here, we report the cryo-EM structure of the human GIPR in complex with GIP and a Gs heterotrimer at a global resolution of 2.9 Å. GIP adopts a single straight helix with its N terminus dipped into the receptor transmembrane domain (TMD), while the C terminus is closely associated with the extracellular domain and extracellular loop 1. GIPR employs conserved residues in the lower half of the TMD pocket to recognize the common segments shared by GIP homologous peptides, while uses non-conserved residues in the upper half of the TMD pocket to interact with residues specific for GIP. These results provide a structural framework of hormone recognition and GIPR activation. |
| first_indexed | 2024-04-12T02:18:34Z |
| format | Article |
| id | doaj.art-0967668657d1439e96bdc203b0e58d6e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:18:34Z |
| publishDate | 2021-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0967668657d1439e96bdc203b0e58d6e2022-12-22T03:52:10ZengeLife Sciences Publications LtdeLife2050-084X2021-07-011010.7554/eLife.68719Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptorFenghui Zhao0Chao Zhang1Qingtong Zhou2https://orcid.org/0000-0001-8124-3079Kaini Hang3Xinyu Zou4Yan Chen5Fan Wu6Qidi Rao7Antao Dai8Wanchao Yin9Dan-Dan Shen10Yan Zhang11Tian Xia12Raymond C Stevens13H Eric Xu14Dehua Yang15https://orcid.org/0000-0003-3028-3243Lihua Zhao16Ming-Wei Wang17https://orcid.org/0000-0001-6550-9017School of Pharmacy, Fudan University, Shanghai, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai, China; University of Chinese Academy of Sciences, Beijing, ChinaDepartment of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaSchool of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, ChinaSchool of Pharmacy, Fudan University, Shanghai, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai, China; University of Chinese Academy of Sciences, Beijing, ChinaThe National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaThe CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaDepartment of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaDepartment of Biophysics and Department of Pathology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaSchool of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai, ChinaThe CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, ChinaThe CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaThe CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, ChinaSchool of Pharmacy, Fudan University, Shanghai, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China; Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, China; The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaGlucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that exerts crucial metabolic functions by binding and activating its cognate receptor, GIPR. As an important therapeutic target, GIPR has been subjected to intensive structural studies without success. Here, we report the cryo-EM structure of the human GIPR in complex with GIP and a Gs heterotrimer at a global resolution of 2.9 Å. GIP adopts a single straight helix with its N terminus dipped into the receptor transmembrane domain (TMD), while the C terminus is closely associated with the extracellular domain and extracellular loop 1. GIPR employs conserved residues in the lower half of the TMD pocket to recognize the common segments shared by GIP homologous peptides, while uses non-conserved residues in the upper half of the TMD pocket to interact with residues specific for GIP. These results provide a structural framework of hormone recognition and GIPR activation.https://elifesciences.org/articles/68719glucose-dependent insulinotropic polypeptide receptorcryo-electron microscopyG protein-coupled receptorligand recognition |
| spellingShingle | Fenghui Zhao Chao Zhang Qingtong Zhou Kaini Hang Xinyu Zou Yan Chen Fan Wu Qidi Rao Antao Dai Wanchao Yin Dan-Dan Shen Yan Zhang Tian Xia Raymond C Stevens H Eric Xu Dehua Yang Lihua Zhao Ming-Wei Wang Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor eLife glucose-dependent insulinotropic polypeptide receptor cryo-electron microscopy G protein-coupled receptor ligand recognition |
| title | Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor |
| title_full | Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor |
| title_fullStr | Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor |
| title_full_unstemmed | Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor |
| title_short | Structural insights into hormone recognition by the human glucose-dependent insulinotropic polypeptide receptor |
| title_sort | structural insights into hormone recognition by the human glucose dependent insulinotropic polypeptide receptor |
| topic | glucose-dependent insulinotropic polypeptide receptor cryo-electron microscopy G protein-coupled receptor ligand recognition |
| url | https://elifesciences.org/articles/68719 |
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