Crystal structures of agonist-bound human cannabinoid receptor CB 1

Tian Hua; Kiran Vemuri; Spyros P. Nikas; Robert B. Laprairie; Yiran Wu; Lu Qu; Mengchen Pu; Anisha Korde; Shan Jiang; Jo Hao Ho; Gye Won Han; Kang Ding; Xuanxuan Li; Haiguang Liu; Michæl A. Hanson; Suwen Zhao; Laura M. Bohn; Alexandros Makriyannis; Raymond C. Stevens; Zhi Jie Liu

doi:10.1038/nature23272

Crystal structures of agonist-bound human cannabinoid receptor CB 1

Tian Hua, Kiran Vemuri, Spyros P. Nikas, Robert B. Laprairie, Yiran Wu, Lu Qu, Mengchen Pu, Anisha Korde, Shan Jiang, Jo Hao Ho, Gye Won Han, Kang Ding, Xuanxuan Li, Haiguang Liu, Michæl A. Hanson, Suwen Zhao, Laura M. Bohn, Alexandros Makriyannis, Raymond C. Stevens, Zhi Jie Liu

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379 Citations (Scopus)

Résumé

The cannabinoid receptor 1 (CB 1) is the principal target of the psychoactive constituent of marijuana, the partial agonist " 9 -tetrahydrocannabinol (Δ9 -THC). Here we report two agonist-bound crystal structures of human CB 1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB 1 -agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a Δ twin toggle switch' of Phe200 3.36 and Trp356 6.48 (superscripts denote Ballesteros-Weinstein numbering) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB 1 and provide a molecular basis for predicting the binding modes of Δ9 -THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB 1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

Langue d'origine	English
Pages (de-à)	468-471
Nombre de pages	4
Journal	Nature
Volume	547
Numéro de publication	7664
DOI	https://doi.org/10.1038/nature23272
Statut de publication	Published - juill. 27 2017
Publié à l'externe	Oui

Note bibliographique

Funding Information:
This work was supported by the NSF of China grant 31330019 (Z.-J.L.), the MOST of China grants 2014CB910400 (Z.-J.L.) and 2015CB910104 (Z.-J.L.), NSF of Shanghai 16ZR1448500 grant (S.Z.), Key R&D Program of China grant 2016YCF0905902 (S.Z.), NIH grants R01DA041435 (R.C.S., A.M.), P01DA009158 (A.M., L.M.B.), R37DA023142 (A.M.), NSF grants, Shanghai Municipal Government, ShanghaiTech University and GPCR Consortium. The diffraction data were collected at GM/CA@APS of Argonne National Laboratory, X06SA@SLS of the Paul Scherrer Insitute, and BL41XU@ Spring-8 with JASRI proposals 2015B1031 and 2016A2731. We thank M. Wang, C.-Y. Huang, V. Olieric, M. Audet and M.-Y. Lee for their help with data collection, A. Walker for critical review of the manuscript, and F. Sun for high-resolution mass spectrometry analysis.

Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

ASJC Scopus Subject Areas

General

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

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10.1038/nature23272

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Hua, T., Vemuri, K., Nikas, S. P., Laprairie, R. B., Wu, Y., Qu, L., Pu, M., Korde, A., Jiang, S., Ho, J. H., Han, G. W., Ding, K., Li, X., Liu, H., Hanson, M. A., Zhao, S., Bohn, L. M., Makriyannis, A., Stevens, R. C., & Liu, Z. J. (2017). Crystal structures of agonist-bound human cannabinoid receptor CB 1. Nature, 547(7664), 468-471. https://doi.org/10.1038/nature23272

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title = "Crystal structures of agonist-bound human cannabinoid receptor CB 1",

abstract = "The cannabinoid receptor 1 (CB 1) is the principal target of the psychoactive constituent of marijuana, the partial agonist {"} 9 -tetrahydrocannabinol (Δ9 -THC). Here we report two agonist-bound crystal structures of human CB 1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 {\AA} and 2.95 {\AA} resolution, respectively. The two CB 1 -agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a Δ twin toggle switch' of Phe200 3.36 and Trp356 6.48 (superscripts denote Ballesteros-Weinstein numbering) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB 1 and provide a molecular basis for predicting the binding modes of Δ9 -THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB 1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.",

author = "Tian Hua and Kiran Vemuri and Nikas, {Spyros P.} and Laprairie, {Robert B.} and Yiran Wu and Lu Qu and Mengchen Pu and Anisha Korde and Shan Jiang and Ho, {Jo Hao} and Han, {Gye Won} and Kang Ding and Xuanxuan Li and Haiguang Liu and Hanson, {Mich{\ae}l A.} and Suwen Zhao and Bohn, {Laura M.} and Alexandros Makriyannis and Stevens, {Raymond C.} and Liu, {Zhi Jie}",

note = "Funding Information: This work was supported by the NSF of China grant 31330019 (Z.-J.L.), the MOST of China grants 2014CB910400 (Z.-J.L.) and 2015CB910104 (Z.-J.L.), NSF of Shanghai 16ZR1448500 grant (S.Z.), Key R&D Program of China grant 2016YCF0905902 (S.Z.), NIH grants R01DA041435 (R.C.S., A.M.), P01DA009158 (A.M., L.M.B.), R37DA023142 (A.M.), NSF grants, Shanghai Municipal Government, ShanghaiTech University and GPCR Consortium. The diffraction data were collected at GM/CA@APS of Argonne National Laboratory, X06SA@SLS of the Paul Scherrer Insitute, and BL41XU@ Spring-8 with JASRI proposals 2015B1031 and 2016A2731. We thank M. Wang, C.-Y. Huang, V. Olieric, M. Audet and M.-Y. Lee for their help with data collection, A. Walker for critical review of the manuscript, and F. Sun for high-resolution mass spectrometry analysis. Publisher Copyright: {\textcopyright} 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.",

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doi = "10.1038/nature23272",

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T1 - Crystal structures of agonist-bound human cannabinoid receptor CB 1

AU - Hua, Tian

AU - Vemuri, Kiran

AU - Nikas, Spyros P.

AU - Laprairie, Robert B.

AU - Wu, Yiran

AU - Qu, Lu

AU - Pu, Mengchen

AU - Korde, Anisha

AU - Jiang, Shan

AU - Ho, Jo Hao

AU - Han, Gye Won

AU - Ding, Kang

AU - Li, Xuanxuan

AU - Liu, Haiguang

AU - Hanson, Michæl A.

AU - Zhao, Suwen

AU - Bohn, Laura M.

AU - Makriyannis, Alexandros

AU - Stevens, Raymond C.

AU - Liu, Zhi Jie

N1 - Funding Information: This work was supported by the NSF of China grant 31330019 (Z.-J.L.), the MOST of China grants 2014CB910400 (Z.-J.L.) and 2015CB910104 (Z.-J.L.), NSF of Shanghai 16ZR1448500 grant (S.Z.), Key R&D Program of China grant 2016YCF0905902 (S.Z.), NIH grants R01DA041435 (R.C.S., A.M.), P01DA009158 (A.M., L.M.B.), R37DA023142 (A.M.), NSF grants, Shanghai Municipal Government, ShanghaiTech University and GPCR Consortium. The diffraction data were collected at GM/CA@APS of Argonne National Laboratory, X06SA@SLS of the Paul Scherrer Insitute, and BL41XU@ Spring-8 with JASRI proposals 2015B1031 and 2016A2731. We thank M. Wang, C.-Y. Huang, V. Olieric, M. Audet and M.-Y. Lee for their help with data collection, A. Walker for critical review of the manuscript, and F. Sun for high-resolution mass spectrometry analysis. Publisher Copyright: © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

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N2 - The cannabinoid receptor 1 (CB 1) is the principal target of the psychoactive constituent of marijuana, the partial agonist " 9 -tetrahydrocannabinol (Δ9 -THC). Here we report two agonist-bound crystal structures of human CB 1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB 1 -agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a Δ twin toggle switch' of Phe200 3.36 and Trp356 6.48 (superscripts denote Ballesteros-Weinstein numbering) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB 1 and provide a molecular basis for predicting the binding modes of Δ9 -THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB 1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.

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Crystal structures of agonist-bound human cannabinoid receptor CB 1

Résumé

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ASJC Scopus Subject Areas

PubMed: MeSH publication types

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