Structure of the human galanin receptor 2 bound to galanin and Gq reveals the basis of ligand specificity and how binding affects the G-protein interface

Yunseok Heo; Naito Ishimoto; Ye Eun Jeon; Ji Hye Yun; Mio Ohki; Yuki Anraku; Mina Sasaki; Shunsuke Kita; Hideo Fukuhara; Tatsuya Ikuta; Kouki Kawakami; Asuka Inoue; Katsumi Maenaka; Jeremy R.H. Tame; Weontae Lee; Sam Yong Park

doi:10.1371/journal.pbio.3001714

Structure of the human galanin receptor 2 bound to galanin and Gq reveals the basis of ligand specificity and how binding affects the G-protein interface

Yunseok Heo, Naito Ishimoto, Ye Eun Jeon, Ji Hye Yun, Mio Ohki, Yuki Anraku, Mina Sasaki, Shunsuke Kita, Hideo Fukuhara, Tatsuya Ikuta, Kouki Kawakami, Asuka Inoue, Katsumi Maenaka, Jeremy R.H. Tame, Weontae Lee, Sam Yong Park

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Abstract

Galanin is a neuropeptide expressed in the central and peripheral nervous systems, where it regulates various processes including neuroendocrine release, cognition, and nerve regeneration. Three G-protein coupled receptors (GPCRs) for galanin have been discovered, which is the focus of efforts to treat diseases including Alzheimer's disease, anxiety, and addiction. To understand the basis of the ligand preferences of the receptors and to assist structure-based drug design, we used cryo-electron microscopy (cryo-EM) to solve the molecular structure of GALR2 bound to galanin and a cognate heterotrimeric G-protein, providing a molecular view of the neuropeptide binding site. Mutant proteins were assayed to help reveal the basis of ligand specificity, and structural comparison between the activated GALR2 and inactive hβ2AR was used to relate galanin binding to the movements of transmembrane (TM) helices and the G-protein interface.

Original language	English
Article number	e3001714
Journal	PLoS Biology
Volume	20
Issue number	8
DOIs	https://doi.org/10.1371/journal.pbio.3001714
Publication status	Published - 2022 Aug

Bibliographical note

Publisher Copyright:
© 2022 Heo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

All Science Journal Classification (ASJC) codes

Neuroscience(all)
Biochemistry, Genetics and Molecular Biology(all)
Immunology and Microbiology(all)
Agricultural and Biological Sciences(all)

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10.1371/journal.pbio.3001714

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Heo, Y., Ishimoto, N., Jeon, Y. E., Yun, J. H., Ohki, M., Anraku, Y., Sasaki, M., Kita, S., Fukuhara, H., Ikuta, T., Kawakami, K., Inoue, A., Maenaka, K., Tame, J. R. H., Lee, W., & Park, S. Y. (2022). Structure of the human galanin receptor 2 bound to galanin and Gq reveals the basis of ligand specificity and how binding affects the G-protein interface. PLoS Biology, 20(8), [e3001714]. https://doi.org/10.1371/journal.pbio.3001714

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abstract = "Galanin is a neuropeptide expressed in the central and peripheral nervous systems, where it regulates various processes including neuroendocrine release, cognition, and nerve regeneration. Three G-protein coupled receptors (GPCRs) for galanin have been discovered, which is the focus of efforts to treat diseases including Alzheimer's disease, anxiety, and addiction. To understand the basis of the ligand preferences of the receptors and to assist structure-based drug design, we used cryo-electron microscopy (cryo-EM) to solve the molecular structure of GALR2 bound to galanin and a cognate heterotrimeric G-protein, providing a molecular view of the neuropeptide binding site. Mutant proteins were assayed to help reveal the basis of ligand specificity, and structural comparison between the activated GALR2 and inactive hβ2AR was used to relate galanin binding to the movements of transmembrane (TM) helices and the G-protein interface.",

author = "Yunseok Heo and Naito Ishimoto and Jeon, {Ye Eun} and Yun, {Ji Hye} and Mio Ohki and Yuki Anraku and Mina Sasaki and Shunsuke Kita and Hideo Fukuhara and Tatsuya Ikuta and Kouki Kawakami and Asuka Inoue and Katsumi Maenaka and Tame, {Jeremy R.H.} and Weontae Lee and Park, {Sam Yong}",

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Heo, Y, Ishimoto, N, Jeon, YE, Yun, JH, Ohki, M, Anraku, Y, Sasaki, M, Kita, S, Fukuhara, H, Ikuta, T, Kawakami, K, Inoue, A, Maenaka, K, Tame, JRH, Lee, W & Park, SY 2022, 'Structure of the human galanin receptor 2 bound to galanin and Gq reveals the basis of ligand specificity and how binding affects the G-protein interface', PLoS Biology, vol. 20, no. 8, e3001714. https://doi.org/10.1371/journal.pbio.3001714

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AU - Inoue, Asuka

AU - Maenaka, Katsumi

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AU - Lee, Weontae

AU - Park, Sam Yong

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Structure of the human galanin receptor 2 bound to galanin and Gq reveals the basis of ligand specificity and how binding affects the G-protein interface

Abstract

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