GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors

Research output: Contribution to journal › Journal article › Research › peer-review

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GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors. / Huang, Sijie; Xu, Peiyu; Shen, Dan-Dan; Simon, Icaro A; Mao, Chunyou; Tan, Yangxia; Zhang, Huibing; Harpsøe, Kasper; Li, Huadong; Zhang, Yumu; You, Chongzhao; Yu, Xuekui; Jiang, Yi; Zhang, Yan; Gloriam, David E; Xu, H Eric.

In: Molecular Cell, Vol. 82, No. 14, 2022, p. 2681-2695.e6.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Huang, S, Xu, P, Shen, D-D, Simon, IA, Mao, C, Tan, Y, Zhang, H, Harpsøe, K, Li, H, Zhang, Y, You, C, Yu, X, Jiang, Y, Zhang, Y, Gloriam, DE & Xu, HE 2022, 'GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors', Molecular Cell, vol. 82, no. 14, pp. 2681-2695.e6. https://doi.org/10.1016/j.molcel.2022.05.031

APA

Huang, S., Xu, P., Shen, D-D., Simon, I. A., Mao, C., Tan, Y., Zhang, H., Harpsøe, K., Li, H., Zhang, Y., You, C., Yu, X., Jiang, Y., Zhang, Y., Gloriam, D. E., & Xu, H. E. (2022). GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors. Molecular Cell, 82(14), 2681-2695.e6. https://doi.org/10.1016/j.molcel.2022.05.031

Vancouver

Huang S, Xu P, Shen D-D, Simon IA, Mao C, Tan Y et al. GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors. Molecular Cell. 2022;82(14):2681-2695.e6. https://doi.org/10.1016/j.molcel.2022.05.031

Author

Huang, Sijie ; Xu, Peiyu ; Shen, Dan-Dan ; Simon, Icaro A ; Mao, Chunyou ; Tan, Yangxia ; Zhang, Huibing ; Harpsøe, Kasper ; Li, Huadong ; Zhang, Yumu ; You, Chongzhao ; Yu, Xuekui ; Jiang, Yi ; Zhang, Yan ; Gloriam, David E ; Xu, H Eric. / GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors. In: Molecular Cell. 2022 ; Vol. 82, No. 14. pp. 2681-2695.e6.

Bibtex

@article{6e5ad16f29f24e0b8069aa3c9c406248,

title = "GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors",

abstract = "Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of Gs, Gi, or Gq proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 with Gi1. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for Gs and Gi, respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with Gs or Gi. Together, these results present a common mechanism of Gs versus Gi protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors.",

author = "Sijie Huang and Peiyu Xu and Dan-Dan Shen and Simon, {Icaro A} and Chunyou Mao and Yangxia Tan and Huibing Zhang and Kasper Harps{\o}e and Huadong Li and Yumu Zhang and Chongzhao You and Xuekui Yu and Yi Jiang and Yan Zhang and Gloriam, {David E} and Xu, {H Eric}",

year = "2022",

doi = "10.1016/j.molcel.2022.05.031",

language = "English",

volume = "82",

pages = "2681--2695.e6",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "14",

}

RIS

TY - JOUR

T1 - GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors

AU - Huang, Sijie

AU - Xu, Peiyu

AU - Shen, Dan-Dan

AU - Simon, Icaro A

AU - Mao, Chunyou

AU - Tan, Yangxia

AU - Zhang, Huibing

AU - Harpsøe, Kasper

AU - Li, Huadong

AU - Zhang, Yumu

AU - You, Chongzhao

AU - Yu, Xuekui

AU - Jiang, Yi

AU - Zhang, Yan

AU - Gloriam, David E

AU - Xu, H Eric

PY - 2022

Y1 - 2022

N2 - Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of Gs, Gi, or Gq proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 with Gi1. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for Gs and Gi, respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with Gs or Gi. Together, these results present a common mechanism of Gs versus Gi protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors.

AB - Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of Gs, Gi, or Gq proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT4, 5-HT6, and 5-HT7 with Gs, and 5-HT4 with Gi1. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for Gs and Gi, respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with Gs or Gi. Together, these results present a common mechanism of Gs versus Gi protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors.

U2 - 10.1016/j.molcel.2022.05.031

DO - 10.1016/j.molcel.2022.05.031

M3 - Journal article

C2 - 35714614

VL - 82

SP - 2681-2695.e6

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 14

ER -

ID: 311999814