Advertisement

Cannabinoid Interactions with Proteins: Insights from Structural Studies

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

Abstract

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.

Keywords

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

Abbreviations

2-AG

2-arachidonoylglycerol

AEA

anandamide

CB1

cannabinoid receptor type 1

CB2

cannabinoid receptor type 2

CRBP2

cellular retinol binding protein 2

cryo-EM

cryogenic electron microscopy

ECL

extracellular loop

FABP

fatty acid-binding protein

GPCR

G protein-coupled receptor

ICL

intracellular loop

NMR

nuclear magnetic resonance

PDB

protein data bank

PPAR

peroxisome proliferator-activated receptor

THC

delta9-tetrahydrocannabinol

TM

transmembrane

Notes

Acknowledgements

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.

References

  1. 1.
    Shevyrin V, Melkozerov V, Endres GW, Shafran Y, Morzherin Y (2016) On a new cannabinoid classification system: a sight on the illegal market of novel psychoactive substances. Cannabis Cannabinoid Res 1(1):186–194.  https://doi.org/10.1089/can.2016.0004 CrossRefGoogle Scholar
  2. 2.
    Reggio PH (2002) Endocannabinoid structure-activity relationships for interaction at the cannabinoid receptors. Prostaglandins Leukot Essent Fatty Acids 66:143–160CrossRefGoogle Scholar
  3. 3.
    Wiley JL, Marusich JA, Thomas BF (2017) Combination chemistry: structure-activity relationships of novel psychoactive cannabinoids. Curr Top Behav Neurosci 32:231–248CrossRefGoogle Scholar
  4. 4.
    Paulke A, Proschak E, Sommer K, Achenbach J, Wunder C, Toennes SW (2016) Synthetic cannabinoids: in silico prediction of the cannabinoid receptor 1 affinity by a quantitative structure-activity relationship model. Toxicol Lett 245:1–6CrossRefGoogle Scholar
  5. 5.
    Janero DR, Korde A, Makriyannis A (2017) Ligand-assisted protein structure (LAPS): an experimental paradigm for characterizing cannabinoid-receptor ligand-binding domains. Methods Enzymol 593:217–235CrossRefGoogle Scholar
  6. 6.
    Muller C, Morales P, Reggio PH (2019) Cannabinoid ligands targeting TRP channels. Front Mol Neurosci 11:487CrossRefGoogle Scholar
  7. 7.
    Pertwee RG (2007) GPR55: a new member of the cannabinoid receptor clan? Br J Pharmacol 152:984–986CrossRefGoogle Scholar
  8. 8.
    Morales P, Reggio PH (2017) An update on non-CB1, non-CB2 cannabinoid related G-protein-coupled receptors. Cannabis Cannabinoid Res 2:265–273CrossRefGoogle Scholar
  9. 9.
    Console-Bram L, Marcu J, Abood ME (2012) Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuro-Psychopharmacol Biol Psychiatry 38:4–15CrossRefGoogle Scholar
  10. 10.
    Maroon J, Bost J (2018) Review of the neurological benefits of phytocannabinoids. Surg Neurol Int 9:91CrossRefGoogle Scholar
  11. 11.
    Niemi MH, Turunen L, Pulli T, Nevanen TK, Höyhtyä M, Söderlund H, Rouvinen J, Takkinen K (2010) A structural insight into the molecular recognition of a (-)-Delta9-tetrahydrocannabinol and the development of a sensitive, one-step, homogeneous immunocomplex-based assay for its detection. J Mol Biol 400:803–814CrossRefGoogle Scholar
  12. 12.
    Luchicchi A, Pistis M (2012) Anandamide and 2-arachidonoylglycerol: pharmacological properties, functional features, and emerging specificities of the two major endocannabinoids. Mol Neurobiol 46:374–392CrossRefGoogle Scholar
  13. 13.
    Chmurzyńska A (2006) The multigene family of fatty acid-binding proteins (FABPs): function, structure and polymorphism. J Appl Genet 47:39–48CrossRefGoogle Scholar
  14. 14.
    Elmes MW, Kaczocha M, Berger WT, Leung K, Ralph BP, Wang L, Sweeney JM, Miyauchi JT, Tsirka SE, Ojima I, Deutsch DG (2015) Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem 290:8711–8721CrossRefGoogle Scholar
  15. 15.
    Wang YT, Liu CH, Zhu HL (2016) Fatty acid binding protein (FABP) inhibitors: a patent review (2012-2015). Expert Opin Ther Pat 26:767–776CrossRefGoogle Scholar
  16. 16.
    Amiri M, Yousefnia S, Seyed Forootan F, Peymani M, Ghaedi K, Nasr Esfahani MH (2018) Diverse roles of fatty acid binding proteins (FABPs) in development and pathogenesis of cancers. Gene 676:171–183CrossRefGoogle Scholar
  17. 17.
    Berger WT, Ralph BP, Kaczocha M, Sun J, Balius TE, Rizzo RC, Haj-Dahmane S, Ojima I, Deutsch DG (2012) Targeting fatty acid binding protein (FABP) anandamide transporters – a novel strategy for development of anti-inflammatory and anti-nociceptive drugs. PLoS One 7:e50968CrossRefGoogle Scholar
  18. 18.
    Sanson B, Wang T, Sun J, Wang L, Kaczocha M, Ojima I, Deutsch D, Li H (2014) Crystallographic study of FABP5 as an intracellular endocannabinoid transporter. Acta Crystallogr D Biol Crystallogr 70:290–298CrossRefGoogle Scholar
  19. 19.
    Furuhashi M, Hotamisligil GS (2008) Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 7:489–503CrossRefGoogle Scholar
  20. 20.
    Silvaroli JA, Blaner WS, Lodowski DT, Golczak M (To be published) Crystal structure of human cellular retinol binding protein 2 (CRBP2) in complex with 2-arachidonoylglycerol (2-AG).  https://doi.org/10.2210/pdb6BTH/pdb
  21. 21.
    Ong DE (1987) Cellular retinoid-binding proteins. Arch Dermatol 123:1693–165aCrossRefGoogle Scholar
  22. 22.
    Napoli JL (2017) Cellular retinoid binding-proteins, CRBP, CRABP, FABP5: effects on retinoid metabolism, function and related diseases. Pharmacol Ther 173:19–33CrossRefGoogle Scholar
  23. 23.
    Davidson C, Opacka-Juffry J, Arevalo-Martin A, Garcia-Ovejero D, Molina-Holgado E, Molina-Holgado F (2017) Spicing up pharmacology: a review of synthetic cannabinoids from structure to adverse events. Adv Pharmacol 80:135–168CrossRefGoogle Scholar
  24. 24.
    Freund SA, Banning AS (2017) Synthetic cannabinoids: a review of the clinical implications of a new drug of choice. JAAPA 30:1–4CrossRefGoogle Scholar
  25. 25.
    Cohen K, Weinstein AM (2018) Synthetic and non-synthetic cannabinoid drugs and their adverse effects-a review from public health prospective. Front Public Health 6:162CrossRefGoogle Scholar
  26. 26.
    Ambrosio AL, Dias SM, Polikarpov I, Zurier RB, Burstein SH, Garratt RC (2007) Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma. J Biol Chem 282:18625–18633CrossRefGoogle Scholar
  27. 27.
    Bidinger B, Torres R, Rossetti RG, Brown L, Beltre R, Burstein S, Lian JB, Stein GS, Zurier RB (2003) Ajulemic acid, a nonpsychoactive cannabinoid acid, induces apoptosis in human T lymphocytes. Clin Immunol 108:95–102CrossRefGoogle Scholar
  28. 28.
    Liu J, Li H, Burstein SH, Zurier RB, Chen JD (2003) Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid. Mol Pharmacol 63:983–992CrossRefGoogle Scholar
  29. 29.
    Zurier RB, Rossetti RG, Burstein SH, Bidinger B (2003) Suppression of human monocyte interleukin-1beta production by ajulemic acid, a nonpsychoactive cannabinoid. Biochem Pharmacol 65:649–655CrossRefGoogle Scholar
  30. 30.
    Lefterova MI, Haakonsson AK, Lazar MA, Mandrup S (2014) PPARγ and the global map of adipogenesis and beyond. Trends Endocrinol Metab 25:293–302CrossRefGoogle Scholar
  31. 31.
    Wang S, Dougherty EJ, Danner RL (2016) PPARγ signaling and emerging opportunities for improved therapeutics. Pharmacol Res 111:76–85CrossRefGoogle Scholar
  32. 32.
    Han L, Shen WJ, Bittner S, Kraemer FB, Azhar S (2017) PPARs: regulators of metabolism and as therapeutic targets in cardiovascular disease. Part II: PPAR-β/δ and PPAR-γ. Futur Cardiol 13:279–296CrossRefGoogle Scholar
  33. 33.
    Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV (1998) Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature 395:137–143CrossRefGoogle Scholar
  34. 34.
    Uppenberg J, Svensson C, Jaki M, Bertilsson G, Jendeberg L, Berkenstam A (1998) Crystal structure of the ligand binding domain of the human nuclear receptor PPARgamma. J Biol Chem 273:31108–31112CrossRefGoogle Scholar
  35. 35.
    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 167:750–762CrossRefGoogle Scholar
  36. 36.
    Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J, Rosenbaum DM (2016) High-resolution crystal structure of the human CB1 cannabinoid receptor. Nature 540(7634):602–606CrossRefGoogle Scholar
  37. 37.
    Price MR, Baillie GL, Thomas A, Stevenson LA, Easson M, Goodwin R, McLean A, McIntosh L, Goodwin G, Walker G, Westwood P, Marrs J, Thomson F, Cowley P, Christopoulos A, Pertwee RG, Ross RA (2005) Allosteric modulation of the cannabinoid CB1 receptor. Mol Pharmacol 68:1484–1495CrossRefGoogle Scholar
  38. 38.
    Khurana L, Mackie K, Piomelli D, Kendall DA (2017) Modulation of CB1 cannabinoid receptor by allosteric ligands: pharmacology and therapeutic opportunities. Neuropharmacology 124:3–12CrossRefGoogle Scholar
  39. 39.
    Nguyen T, Li JX, Thomas BF, Wiley JL, Kenakin TP, Zhang Y (2017) Allosteric modulation: an alternate approach targeting the cannabinoid CB1 receptor. Med Res Rev 37:441–474CrossRefGoogle Scholar
  40. 40.
    Scott CE, Kendall DA (2017) Assessing allosteric modulation of CB1 at the receptor and cellular levels. Methods Enzymol 593:317–342CrossRefGoogle Scholar
  41. 41.
    Krishna Kumar K, Shalev-Benami M, Robertson MJ, Hu H, Banister SD, Hollingsworth SA, Latorraca NR, Kato HE, Hilger D, Maeda S, Weis WI, Farrens DL, Dror RO, Malhotra SV, Kobilka BK, Skiniotis G (2019) Structure of a signaling cannabinoid receptor 1-G protein complex. Cell 176:448–458CrossRefGoogle Scholar
  42. 42.
    Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R (2017) “Zombie” outbreak caused by the synthetic cannabinoid AMB-FUBINACA in New York. N Engl J Med 376:235–242CrossRefGoogle Scholar
  43. 43.
    Schoeder CT, Hess C, Madea B, Meiler J, Müller CE (2018) Pharmacological evaluation of new constituents of “spice”: synthetic cannabinoids based on indole, indazole, benzimidazole and carbazole scaffolds. Forensic Toxicol 36:385–403CrossRefGoogle Scholar
  44. 44.
    Ballesteros J, Weinstein H (1995) Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Method Neurosci 25:366–428CrossRefGoogle Scholar
  45. 45.
    Hua T, Vemuri K, Nikas SP, Laprairie RB, Wu Y, Qu L, Pu M, Korde A, Jiang S, Ho JH, Han GW, Ding K, Li X, Liu H, Hanson MA, Zhao S, Bohn LM, Makriyannis A, Stevens RC, Liu ZJ (2017) Crystal structure of the human CB1 in complex with agonist AM841. Nature 547:468–471CrossRefGoogle Scholar
  46. 46.
    Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65CrossRefGoogle Scholar
  47. 47.
    Li X, Hua T, Vemuri K, Ho JH, Wu Y, Wu L, Popov P, Benchama O, Zvonok N, Locke K, Qu L, Han GW, Iyer MR, Cinar R, Coffey NJ, Wang J, Wu M, Katritch V, Zhao S, Kunos G, Bohn LM, Makriyannis A, Stevens RC, Liu ZJ (2019) Crystal structure of the human cannabinoid receptor CB2. Cell 176:459–467CrossRefGoogle Scholar
  48. 48.
    Wiley JL, Marusich JA, Huffman JW (2014) Moving around the molecule: relationship between chemical structure and in vivo activity of synthetic cannabinoids. Life Sci 97:55–63CrossRefGoogle Scholar
  49. 49.
    Mercier RW, Pei Y, Pandarinathan L, Janero DR, Zhang J, Makriyannis A (2010) hCB2 ligand-interaction landscape: cysteine residues critical to biarylpyrazole antagonist binding motif and receptor modulation. Chem Biol 17:1132–1142CrossRefGoogle Scholar
  50. 50.
    Jensen MØ, Mouritsen OG (2004) Lipids do influence protein function-the hydrophobic matching hypothesis revisited. Biochim Biophys Acta 1666:205–226CrossRefGoogle Scholar
  51. 51.
    Lee AG (2004) How lipids affect the activities of integral membrane proteins. Biochim Biophys Acta 1666:62–87CrossRefGoogle Scholar
  52. 52.
    Khan MS, Dosoky NS, Williams JD (2013) Engineering lipid bilayer membranes for protein studies. Int J Mol Sci 14:21561–21597CrossRefGoogle Scholar
  53. 53.
    Di Scala C, Fantini J, Yahi N, Barrantes FJ, Chahinian H (2018) Anandamide revisited: how cholesterol and ceramides control receptor-dependent and receptor-independent signal transmission pathways of a lipid neurotransmitter. Biomolecules 8(2):31CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

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

Personalised recommendations