Structural insights into the lipid and ligand regulation of serotonin receptors

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

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Structural insights into the lipid and ligand regulation of serotonin receptors. / Xu, Peiyu; Huang, Sijie; Zhang, Huibing; Mao, Chunyou; Zhou, X Edward; Cheng, Xi; Simon, Icaro A; Shen, Dan-Dan; Yen, Hsin-Yung; Robinson, Carol V; Harpsøe, Kasper; Svensson, Bo; Guo, Jia; Jiang, Hualiang; Gloriam, David E; Melcher, Karsten; Jiang, Yi; Zhang, Yan; Xu, H Eric.

In: Nature, Vol. 592, 2021, p. 469-473.

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

Harvard

Xu, P, Huang, S, Zhang, H, Mao, C, Zhou, XE, Cheng, X, Simon, IA, Shen, D-D, Yen, H-Y, Robinson, CV, Harpsøe, K, Svensson, B, Guo, J, Jiang, H, Gloriam, DE, Melcher, K, Jiang, Y, Zhang, Y & Xu, HE 2021, 'Structural insights into the lipid and ligand regulation of serotonin receptors', Nature, vol. 592, pp. 469-473. https://doi.org/10.1038/s41586-021-03376-8

APA

Xu, P., Huang, S., Zhang, H., Mao, C., Zhou, X. E., Cheng, X., Simon, I. A., Shen, D-D., Yen, H-Y., Robinson, C. V., Harpsøe, K., Svensson, B., Guo, J., Jiang, H., Gloriam, D. E., Melcher, K., Jiang, Y., Zhang, Y., & Xu, H. E. (2021). Structural insights into the lipid and ligand regulation of serotonin receptors. Nature, 592, 469-473. https://doi.org/10.1038/s41586-021-03376-8

Vancouver

Xu P, Huang S, Zhang H, Mao C, Zhou XE, Cheng X et al. Structural insights into the lipid and ligand regulation of serotonin receptors. Nature. 2021;592:469-473. https://doi.org/10.1038/s41586-021-03376-8

Author

Xu, Peiyu ; Huang, Sijie ; Zhang, Huibing ; Mao, Chunyou ; Zhou, X Edward ; Cheng, Xi ; Simon, Icaro A ; Shen, Dan-Dan ; Yen, Hsin-Yung ; Robinson, Carol V ; Harpsøe, Kasper ; Svensson, Bo ; Guo, Jia ; Jiang, Hualiang ; Gloriam, David E ; Melcher, Karsten ; Jiang, Yi ; Zhang, Yan ; Xu, H Eric. / Structural insights into the lipid and ligand regulation of serotonin receptors. In: Nature. 2021 ; Vol. 592. pp. 469-473.

Bibtex

@article{f4ac0006b96d438485aecc3ff125e0df,
title = "Structural insights into the lipid and ligand regulation of serotonin receptors",
abstract = "Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter1,2 that activates the largest subtype family of G-protein-coupled receptors3. Drugs that target 5-HT1A, 5-HT1D, 5-HT1E and other 5-HT receptors are used to treat numerous disorders4. 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear. Here we report five structures of 5-HT receptor-G-protein complexes: 5-HT1A in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT1D bound to 5-HT; and 5-HT1E in complex with a 5-HT1E- and 5-HT1F-selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein-5-HT1A interface, and is able to increase 5-HT1A-mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules-particularly in the case of 5-HT1A, in which cholesterol molecules are directly involved in shaping the ligand-binding pocket that determines the specificity for aripiprazol. Within the ligand-binding pocket of apo-5-HT1A are structured water molecules that mimic 5-HT to activate the receptor. Together, our results address a long-standing question of how lipids and water molecules regulate G-protein-coupled receptors, reveal how 5-HT acts as a pan-agonist, and identify the determinants of drug recognition in 5-HT receptors.",
author = "Peiyu Xu and Sijie Huang and Huibing Zhang and Chunyou Mao and Zhou, {X Edward} and Xi Cheng and Simon, {Icaro A} and Dan-Dan Shen and Hsin-Yung Yen and Robinson, {Carol V} and Kasper Harps{\o}e and Bo Svensson and Jia Guo and Hualiang Jiang and Gloriam, {David E} and Karsten Melcher and Yi Jiang and Yan Zhang and Xu, {H Eric}",
year = "2021",
doi = "10.1038/s41586-021-03376-8",
language = "English",
volume = "592",
pages = "469--473",
journal = "Nature",
issn = "0028-0836",
publisher = "nature publishing group",

}

RIS

TY - JOUR

T1 - Structural insights into the lipid and ligand regulation of serotonin receptors

AU - Xu, Peiyu

AU - Huang, Sijie

AU - Zhang, Huibing

AU - Mao, Chunyou

AU - Zhou, X Edward

AU - Cheng, Xi

AU - Simon, Icaro A

AU - Shen, Dan-Dan

AU - Yen, Hsin-Yung

AU - Robinson, Carol V

AU - Harpsøe, Kasper

AU - Svensson, Bo

AU - Guo, Jia

AU - Jiang, Hualiang

AU - Gloriam, David E

AU - Melcher, Karsten

AU - Jiang, Yi

AU - Zhang, Yan

AU - Xu, H Eric

PY - 2021

Y1 - 2021

N2 - Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter1,2 that activates the largest subtype family of G-protein-coupled receptors3. Drugs that target 5-HT1A, 5-HT1D, 5-HT1E and other 5-HT receptors are used to treat numerous disorders4. 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear. Here we report five structures of 5-HT receptor-G-protein complexes: 5-HT1A in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT1D bound to 5-HT; and 5-HT1E in complex with a 5-HT1E- and 5-HT1F-selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein-5-HT1A interface, and is able to increase 5-HT1A-mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules-particularly in the case of 5-HT1A, in which cholesterol molecules are directly involved in shaping the ligand-binding pocket that determines the specificity for aripiprazol. Within the ligand-binding pocket of apo-5-HT1A are structured water molecules that mimic 5-HT to activate the receptor. Together, our results address a long-standing question of how lipids and water molecules regulate G-protein-coupled receptors, reveal how 5-HT acts as a pan-agonist, and identify the determinants of drug recognition in 5-HT receptors.

AB - Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter1,2 that activates the largest subtype family of G-protein-coupled receptors3. Drugs that target 5-HT1A, 5-HT1D, 5-HT1E and other 5-HT receptors are used to treat numerous disorders4. 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear. Here we report five structures of 5-HT receptor-G-protein complexes: 5-HT1A in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT1D bound to 5-HT; and 5-HT1E in complex with a 5-HT1E- and 5-HT1F-selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein-5-HT1A interface, and is able to increase 5-HT1A-mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules-particularly in the case of 5-HT1A, in which cholesterol molecules are directly involved in shaping the ligand-binding pocket that determines the specificity for aripiprazol. Within the ligand-binding pocket of apo-5-HT1A are structured water molecules that mimic 5-HT to activate the receptor. Together, our results address a long-standing question of how lipids and water molecules regulate G-protein-coupled receptors, reveal how 5-HT acts as a pan-agonist, and identify the determinants of drug recognition in 5-HT receptors.

U2 - 10.1038/s41586-021-03376-8

DO - 10.1038/s41586-021-03376-8

M3 - Journal article

C2 - 33762731

VL - 592

SP - 469

EP - 473

JO - Nature

JF - Nature

SN - 0028-0836

ER -

ID: 259934204