Crystal Structure of the Human Cannabinoid Receptor CB1

Tian Hua; Kiran Vemuri; Mengchen Pu; Lu Qu; Gye Won Han; Yiran Wu; Suwen Zhao; Wenqing Shui; Shanshan Li; Anisha Korde; Robert B. Laprairie; Edward L. Stahl; Jo Hao Ho; Nikolai Zvonok; Han Zhou; Irina Kufareva; Beili Wu; Qiang Zhao; Michael A. Hanson; Laura M. Bohn; Alexandros Makriyannis; Raymond C. Stevens; Zhi Jie Liu

doi:10.1016/j.cell.2016.10.004

Crystal Structure of the Human Cannabinoid Receptor CB₁

Tian Hua, Kiran Vemuri, Mengchen Pu, Lu Qu, Gye Won Han, Yiran Wu, Suwen Zhao, Wenqing Shui, Shanshan Li, Anisha Korde, Robert B. Laprairie, Edward L. Stahl, Jo Hao Ho, Nikolai Zvonok, Han Zhou, Irina Kufareva, Beili Wu, Qiang Zhao, Michael A. Hanson, Laura M. BohnAlexandros Makriyannis, Raymond C. Stevens, Zhi Jie Liu

Research output: Contribution to journal › Article › peer-review

424 Citations (Scopus)

Abstract

Cannabinoid receptor 1 (CB₁) is the principal target of Δ⁹-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB₁ is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 Å crystal structure of human CB₁ in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB₁-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB₁ ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB₁ and provides new opportunities for the design of next-generation CB₁-targeting pharmaceuticals.

Original language	English
Pages (from-to)	750-762.e14
Journal	Cell
Volume	167
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2016.10.004
Publication status	Published - Oct 20 2016
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.

ASJC Scopus Subject Areas

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2016.10.004

Cite this

Hua, T, Vemuri, K, Pu, M, Qu, L, Han, GW, Wu, Y, Zhao, S, Shui, W, Li, S, Korde, A, Laprairie, RB, Stahl, EL, Ho, JH, Zvonok, N, Zhou, H, Kufareva, I, Wu, B, Zhao, Q, Hanson, MA, Bohn, LM, Makriyannis, A, Stevens, RC & Liu, ZJ 2016, 'Crystal Structure of the Human Cannabinoid Receptor CB₁', Cell, vol. 167, no. 3, pp. 750-762.e14. https://doi.org/10.1016/j.cell.2016.10.004

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abstract = "Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use. CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. Here, we present the 2.8 {\AA} crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study. The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding. In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids. This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.",

author = "Tian Hua and Kiran Vemuri and Mengchen Pu and Lu Qu and Han, {Gye Won} and Yiran Wu and Suwen Zhao and Wenqing Shui and Shanshan Li and Anisha Korde and Laprairie, {Robert B.} and Stahl, {Edward L.} and Ho, {Jo Hao} and Nikolai Zvonok and Han Zhou and Irina Kufareva and Beili Wu and Qiang Zhao and Hanson, {Michael A.} and Bohn, {Laura M.} and Alexandros Makriyannis and Stevens, {Raymond C.} and Liu, {Zhi Jie}",

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AU - Zhao, Suwen

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AU - Li, Shanshan

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AU - Ho, Jo Hao

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AU - Zhou, Han

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AU - Wu, Beili

AU - Zhao, Qiang

AU - Hanson, Michael A.

AU - Bohn, Laura M.

AU - Makriyannis, Alexandros

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AU - Liu, Zhi Jie

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