GPCR activation and GRK2 assembly by a biased intracellular agonist

doi:10.1038/s41586-023-06395-9

. 2023 Aug;620(7974):676-681.

doi: 10.1038/s41586-023-06395-9. Epub 2023 Aug 2.

GPCR activation and GRK2 assembly by a biased intracellular agonist

Jia Duan^#^{1

2

3}, Heng Liu^#⁴, Fenghui Zhao^#⁵, Qingning Yuan⁴, Yujie Ji^{4

6}, Xiaoqing Cai⁵, Xinheng He^{4

6}, Xinzhu Li⁴, Junrui Li⁴, Kai Wu⁴, Tianyu Gao^{4

7}, Shengnan Zhu⁴, Shi Lin⁸, Ming-Wei Wang⁸, Xi Cheng⁴, Wanchao Yin^{4

9

6}, Yi Jiang¹⁰, Dehua Yang^{11

12

13}, H Eric Xu^{14

15

16}

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. duanjia@simm.ac.cn.
² Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China. duanjia@simm.ac.cn.
³ University of Chinese Academy of Sciences, Beijing, China. duanjia@simm.ac.cn.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁵ The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁶ University of Chinese Academy of Sciences, Beijing, China.
⁷ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁸ Research Center for Deepsea Bioresources, Sanya, Hainan, China.
⁹ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.
¹⁰ Lingang Laboratory, Shanghai, China.
¹¹ University of Chinese Academy of Sciences, Beijing, China. dhyang@simm.ac.cn.
¹² The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. dhyang@simm.ac.cn.
¹³ Research Center for Deepsea Bioresources, Sanya, Hainan, China. dhyang@simm.ac.cn.
¹⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. eric.xu@simm.ac.cn.
¹⁵ University of Chinese Academy of Sciences, Beijing, China. eric.xu@simm.ac.cn.
¹⁶ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. eric.xu@simm.ac.cn.

^# Contributed equally.

PMID: 37532940
DOI: 10.1038/s41586-023-06395-9

GPCR activation and GRK2 assembly by a biased intracellular agonist

Jia Duan et al. Nature. 2023 Aug.

. 2023 Aug;620(7974):676-681.

doi: 10.1038/s41586-023-06395-9. Epub 2023 Aug 2.

Authors

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. duanjia@simm.ac.cn.
² Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China. duanjia@simm.ac.cn.
³ University of Chinese Academy of Sciences, Beijing, China. duanjia@simm.ac.cn.
⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁵ The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁶ University of Chinese Academy of Sciences, Beijing, China.
⁷ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁸ Research Center for Deepsea Bioresources, Sanya, Hainan, China.
⁹ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.
¹⁰ Lingang Laboratory, Shanghai, China.
¹¹ University of Chinese Academy of Sciences, Beijing, China. dhyang@simm.ac.cn.
¹² The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. dhyang@simm.ac.cn.
¹³ Research Center for Deepsea Bioresources, Sanya, Hainan, China. dhyang@simm.ac.cn.
¹⁴ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. eric.xu@simm.ac.cn.
¹⁵ University of Chinese Academy of Sciences, Beijing, China. eric.xu@simm.ac.cn.
¹⁶ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. eric.xu@simm.ac.cn.

^# Contributed equally.

PMID: 37532940
DOI: 10.1038/s41586-023-06395-9

Abstract

Phosphorylation of G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) desensitizes G-protein signalling and promotes arrestin signalling, which is also modulated by biased ligands^1-6. The molecular assembly of GRKs on GPCRs and the basis of GRK-mediated biased signalling remain largely unknown owing to the weak GPCR-GRK interactions. Here we report the complex structure of neurotensin receptor 1 (NTSR1) bound to GRK2, Gα_q and the arrestin-biased ligand SBI-553⁷. The density map reveals the arrangement of the intact GRK2 with the receptor, with the N-terminal helix of GRK2 docking into the open cytoplasmic pocket formed by the outward movement of the receptor transmembrane helix 6, analogous to the binding of the G protein to the receptor. SBI-553 binds at the interface between GRK2 and NTSR1 to enhance GRK2 binding. The binding mode of SBI-553 is compatible with arrestin binding but clashes with the binding of Gα_q protein, thus providing a mechanism for its arrestin-biased signalling capability. In sum, our structure provides a rational model for understanding the details of GPCR-GRK interactions and GRK2-mediated biased signalling.

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References

1. Pitcher, J. A., Freedman, N. J. & Lefkowitz, R. J. G protein-coupled receptor kinases. Annu. Rev. Biochem. 67, 653–692 (1998). - PubMed - DOI
1. Gurevich, E. V., Tesmer, J. J., Mushegian, A. & Gurevich, V. V. G protein-coupled receptor kinases: more than just kinases and not only for GPCRs. Pharmacol. Ther. 133, 40–69 (2012). - PubMed - DOI
1. Gurevich, V. V. & Gurevich, E. V. GPCR signaling regulation: the role of GRKs and arrestins. Front. Pharmacol. 10, 125 (2019). - PubMed - PMC - DOI
1. Hodavance, S. Y., Gareri, C., Torok, R. D. & Rockman, H. A. G protein-coupled receptor biased agonism. J. Cardiovasc. Pharmacol. 67, 193–202 (2016). - PubMed - PMC - DOI
1. Rankovic, Z., Brust, T. F. & Bohn, L. M. Biased agonism: an emerging paradigm in GPCR drug discovery. Bioorg. Med. Chem. Lett. 26, 241–250 (2016). - PubMed - DOI

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[1] Pitcher, J. A., Freedman, N. J. & Lefkowitz, R. J. G protein-coupled receptor kinases. Annu. Rev. Biochem. 67, 653–692 (1998). - PubMed - DOI

[2] Pitcher, J. A., Freedman, N. J. & Lefkowitz, R. J. G protein-coupled receptor kinases. Annu. Rev. Biochem. 67, 653–692 (1998). - PubMed - DOI

[3] Gurevich, E. V., Tesmer, J. J., Mushegian, A. & Gurevich, V. V. G protein-coupled receptor kinases: more than just kinases and not only for GPCRs. Pharmacol. Ther. 133, 40–69 (2012). - PubMed - DOI

[4] Gurevich, E. V., Tesmer, J. J., Mushegian, A. & Gurevich, V. V. G protein-coupled receptor kinases: more than just kinases and not only for GPCRs. Pharmacol. Ther. 133, 40–69 (2012). - PubMed - DOI

[5] Gurevich, V. V. & Gurevich, E. V. GPCR signaling regulation: the role of GRKs and arrestins. Front. Pharmacol. 10, 125 (2019). - PubMed - PMC - DOI

[6] Gurevich, V. V. & Gurevich, E. V. GPCR signaling regulation: the role of GRKs and arrestins. Front. Pharmacol. 10, 125 (2019). - PubMed - PMC - DOI

[7] Hodavance, S. Y., Gareri, C., Torok, R. D. & Rockman, H. A. G protein-coupled receptor biased agonism. J. Cardiovasc. Pharmacol. 67, 193–202 (2016). - PubMed - PMC - DOI

[8] Hodavance, S. Y., Gareri, C., Torok, R. D. & Rockman, H. A. G protein-coupled receptor biased agonism. J. Cardiovasc. Pharmacol. 67, 193–202 (2016). - PubMed - PMC - DOI

[9] Rankovic, Z., Brust, T. F. & Bohn, L. M. Biased agonism: an emerging paradigm in GPCR drug discovery. Bioorg. Med. Chem. Lett. 26, 241–250 (2016). - PubMed - DOI

[10] Rankovic, Z., Brust, T. F. & Bohn, L. M. Biased agonism: an emerging paradigm in GPCR drug discovery. Bioorg. Med. Chem. Lett. 26, 241–250 (2016). - PubMed - DOI

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GPCR activation and GRK2 assembly by a biased intracellular agonist

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GPCR activation and GRK2 assembly by a biased intracellular agonist

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