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Selectivity determinants of GPCR–G-protein binding

Author

Listed:
  • Tilman Flock

    (MRC Laboratory of Molecular Biology
    Fitzwilliam College)

  • Alexander S. Hauser

    (University of Copenhagen)

  • Nadia Lund

    (University of Copenhagen)

  • David E. Gloriam

    (University of Copenhagen)

  • Santhanam Balaji

    (MRC Laboratory of Molecular Biology)

  • M. Madan Babu

    (MRC Laboratory of Molecular Biology)

Abstract

The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.

Suggested Citation

  • Tilman Flock & Alexander S. Hauser & Nadia Lund & David E. Gloriam & Santhanam Balaji & M. Madan Babu, 2017. "Selectivity determinants of GPCR–G-protein binding," Nature, Nature, vol. 545(7654), pages 317-322, May.
  • Handle: RePEc:nat:nature:v:545:y:2017:i:7654:d:10.1038_nature22070
    DOI: 10.1038/nature22070
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    1. Mark J. Wall & Emily Hill & Robert Huckstepp & Kerry Barkan & Giuseppe Deganutti & Michele Leuenberger & Barbara Preti & Ian Winfield & Sabrina Carvalho & Anna Suchankova & Haifeng Wei & Dewi Safitri , 2022. "Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    2. Jia Duan & Dan-Dan Shen & Tingting Zhao & Shimeng Guo & Xinheng He & Wanchao Yin & Peiyu Xu & Yujie Ji & Li-Nan Chen & Jinyu Liu & Huibing Zhang & Qiufeng Liu & Yi Shi & Xi Cheng & Hualiang Jiang & H., 2022. "Molecular basis for allosteric agonism and G protein subtype selectivity of galanin receptors," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Xinyan Zhu & Yu Qian & Xiaowan Li & Zhenmei Xu & Ruixue Xia & Na Wang & Jiale Liang & Han Yin & Anqi Zhang & Changyou Guo & Guangfu Wang & Yuanzheng He, 2022. "Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
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    5. Li-Hua Zhao & Jingyu Lin & Su-Yu Ji & X. Edward Zhou & Chunyou Mao & Dan-Dan Shen & Xinheng He & Peng Xiao & Jinpeng Sun & Karsten Melcher & Yan Zhang & Xiao Yu & H. Eric Xu, 2022. "Structure insights into selective coupling of G protein subtypes by a class B G protein-coupled receptor," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    6. Marin Matic & Pasquale Miglionico & Manae Tatsumi & Asuka Inoue & Francesco Raimondi, 2023. "GPCRome-wide analysis of G-protein-coupling diversity using a computational biology approach," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Kevin M. Knight & Brian E. Krumm & Nicholas J. Kapolka & W. Grant Ludlam & Meng Cui & Sepehr Mani & Iya Prytkova & Elizabeth G. Obarow & Tyler J. Lefevre & Wenyuan Wei & Ning Ma & Xi-Ping Huang & Jona, 2024. "A neurodevelopmental disorder mutation locks G proteins in the transitory pre-activated state," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    8. Yi Cheng & Hong Zhu & Jun Ren & Hai-Yan Wu & Jia-En Yu & Lu-Yang Jin & Hai-Yan Pang & Hai-Tao Pan & Si-Si Luo & Jing Yan & Kai-Xuan Dong & Long-Yun Ye & Cheng-Liang Zhou & Jie-Xue Pan & Zhuo-Xian Meng, 2023. "Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    9. Jie Heng & Yunfei Hu & Guillermo Pérez-Hernández & Asuka Inoue & Jiawei Zhao & Xiuyan Ma & Xiaoou Sun & Kouki Kawakami & Tatsuya Ikuta & Jienv Ding & Yujie Yang & Lujia Zhang & Sijia Peng & Xiaogang N, 2023. "Function and dynamics of the intrinsically disordered carboxyl terminus of β2 adrenergic receptor," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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