Cannabinoid Interactions with Proteins: Insights from Structural Studies

  • Anna N. BukiyaEmail author
  • Alex M. Dopico
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1162)


Cannabinoids have been widely used for recreational and medicinal purposes. The increasing legalization of cannabinoid use and the growing success in Medicinal Chemistry of cannabinoids have fueled recent interest in cannabinoid-sensing sites in receptor proteins. Here, we review structural data from high-resolution cryo-EM and crystallography studies that depict phytocannabinoid, endocannabinoid, and synthetic cannabinoid molecules bound to various proteins. The latter include antigen-binding fragment (Fab), cellular retinol binding protein 2 (CRBP2), fatty acid-binding protein 5 (FABP5), peroxisome proliferator-activated receptor γ (PPAR γ), and cannabinoid receptor types 1 and 2 (CB1 and CB2). Cannabinoid-protein complexes reveal the complex design of cannabinoid binding sites that are usually presented by conventional ligand-binding pockets on respective proteins. However, subtle differences in cannabinoid interaction with amino acids within the binding pocket often result in diverse consequences for protein function. The rapid increase in available structural data on cannabinoid-protein interactions will ultimately direct drug design efforts toward rendering highly potent cannabinoid-related pharmacotherapies that are devoid of side effects.


Lipid-protein interactions Tetrahydrocannabinol Anandamide 2-arachidonoylglycerol Cannabinoid receptor agonist Cannabinoid receptor antagonist G protein-coupled receptor 







cannabinoid receptor type 1


cannabinoid receptor type 2


cellular retinol binding protein 2


cryogenic electron microscopy


extracellular loop


fatty acid-binding protein


G protein-coupled receptor


intracellular loop


nuclear magnetic resonance


protein data bank


peroxisome proliferator-activated receptor







This work was supported by NIH R21 AA022433 (ANB). The authors extend their gratitude Dr. Avia Rosenhouse-Dantsker (University of Illinois at Chicago) for critical reading of the manuscript and Office of Research (The University of Tennessee Health Science Center) for editorial assistance.


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, College of MedicineThe University of Tennessee Health Science CenterMemphisUSA

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