Structural basis for activation of CB1 by an endocannabinoid analog

Kaavya Krishna Kumar; Michael J Robertson; Elina Thadhani; Haoqing Wang; Carl-Mikael Suomivuori; Alexander S Powers; Lipin Ji; Spyros P Nikas; Ron O Dror; Asuka Inoue; Alexandros Makriyannis; Georgios Skiniotis; Brian Kobilka

doi:10.1038/s41467-023-37864-4

Structural basis for activation of CB1 by an endocannabinoid analog

Nat Commun. 2023 May 9;14(1):2672. doi: 10.1038/s41467-023-37864-4.

Authors

Kaavya Krishna Kumar^#¹, Michael J Robertson^#^{1

2}, Elina Thadhani^{1

2

3

4}, Haoqing Wang¹, Carl-Mikael Suomivuori^{1

2

3

4}, Alexander S Powers^{1

2

3

4

5}, Lipin Ji⁶, Spyros P Nikas⁶, Ron O Dror^{1

2

3

4}, Asuka Inoue⁷, Alexandros Makriyannis^{8

9}, Georgios Skiniotis^{10

11

12}, Brian Kobilka¹³

Affiliations

¹ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA.
² Department of Structural Biology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA.
³ Department of Computer Science, Stanford University, Stanford, CA, 94305, USA.
⁴ Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, 94305, USA.
⁵ Department of Chemistry, Stanford University, Stanford, CA, 94305, USA.
⁶ Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA.
⁷ Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, 980-8578, Japan.
⁸ Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, 02115, USA. a.makriyannis@northeastern.edu.
⁹ Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, 02115, USA. a.makriyannis@northeastern.edu.
¹⁰ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. yiorgo@stanford.edu.
¹¹ Department of Structural Biology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. yiorgo@stanford.edu.
¹² Department of Photon Science, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA, 94025, USA. yiorgo@stanford.edu.
¹³ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, CA, 94305, USA. kobilka@stanford.edu.

^# Contributed equally.

Abstract

Endocannabinoids (eCBs) are endogenous ligands of the cannabinoid receptor 1 (CB1), a G protein-coupled receptor that regulates a number of therapeutically relevant physiological responses. Hence, understanding the structural and functional consequences of eCB-CB1 interactions has important implications for designing effective drugs targeting this receptor. To characterize the molecular details of eCB interaction with CB1, we utilized AMG315, an analog of the eCB anandamide to determine the structure of the AMG315-bound CB1 signaling complex. Compared to previous structures, the ligand binding pocket shows some differences. Using docking, molecular dynamics simulations, and signaling assays we investigated the functional consequences of ligand interactions with the "toggle switch" residues F200^3.36 and W356^6.48. Further, we show that ligand-TM2 interactions drive changes to residues on the intracellular side of TM2 and are a determinant of efficacy in activating G protein. These intracellular TM2 rearrangements are unique to CB1 and are exploited by a CB1-specific allosteric modulator.

Publication types

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

MeSH terms

Biological Assay*
Endocannabinoids*
Gene Rearrangement
Ligands
Molecular Dynamics Simulation

Substances

Endocannabinoids
Ligands

Abstract

Publication types

MeSH terms

Substances

Grants and funding