| Structural highlights
Function
[CNR2_HUMAN] Heterotrimeric G protein-coupled receptor for endocannabinoid 2-arachidonoylglycerol mediating inhibition of adenylate cyclase. May function in inflammatory response, nociceptive transmission and bone homeostasis.[1] [2] [3] [4] [GNAI1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[5] [6] [GBG2_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction (By similarity). [GBB1_HUMAN] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.[7]
Publication Abstract from PubMed
Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with Gi, as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.
Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures.,Hua T, Li X, Wu L, Iliopoulos-Tsoutsouvas C, Wang Y, Wu M, Shen L, Johnston CA, Nikas SP, Song F, Song X, Yuan S, Sun Q, Wu Y, Jiang S, Grim TW, Benchama O, Stahl EL, Zvonok N, Zhao S, Bohn LM, Makriyannis A, Liu ZJ Cell. 2020 Jan 28. pii: S0092-8674(20)30055-6. doi: 10.1016/j.cell.2020.01.008. PMID:32004463[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Tao Q, McAllister SD, Andreassi J, Nowell KW, Cabral GA, Hurst DP, Bachtel K, Ekman MC, Reggio PH, Abood ME. Role of a conserved lysine residue in the peripheral cannabinoid receptor (CB2): evidence for subtype specificity. Mol Pharmacol. 1999 Mar;55(3):605-13. PMID:10051546
- ↑ Feng W, Song ZH. Effects of D3.49A, R3.50A, and A6.34E mutations on ligand binding and activation of the cannabinoid-2 (CB2) receptor. Biochem Pharmacol. 2003 Apr 1;65(7):1077-85. PMID:12663043
- ↑ Kishimoto S, Gokoh M, Oka S, Muramatsu M, Kajiwara T, Waku K, Sugiura T. 2-arachidonoylglycerol induces the migration of HL-60 cells differentiated into macrophage-like cells and human peripheral blood monocytes through the cannabinoid CB2 receptor-dependent mechanism. J Biol Chem. 2003 Jul 4;278(27):24469-75. Epub 2003 Apr 23. PMID:12711605 doi:http://dx.doi.org/10.1074/jbc.M301359200
- ↑ Anand U, Otto WR, Sanchez-Herrera D, Facer P, Yiangou Y, Korchev Y, Birch R, Benham C, Bountra C, Chessell IP, Anand P. Cannabinoid receptor CB2 localisation and agonist-mediated inhibition of capsaicin responses in human sensory neurons. Pain. 2008 Sep 15;138(3):667-80. doi: 10.1016/j.pain.2008.06.007. Epub 2008 Aug, 9. PMID:18692962 doi:http://dx.doi.org/10.1016/j.pain.2008.06.007
- ↑ Cho H, Kehrl JH. Localization of Gi alpha proteins in the centrosomes and at the midbody: implication for their role in cell division. J Cell Biol. 2007 Jul 16;178(2):245-55. PMID:17635935 doi:10.1083/jcb.200604114
- ↑ Johnston CA, Siderovski DP. Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):2001-6. Epub 2007 Jan 30. PMID:17264214
- ↑ Johnston CA, Kimple AJ, Giguere PM, Siderovski DP. Structure of the parathyroid hormone receptor C terminus bound to the G-protein dimer Gbeta1gamma2. Structure. 2008 Jul;16(7):1086-94. PMID:18611381 doi:http://dx.doi.org/10.1016/j.str.2008.04.010
- ↑ Hua T, Li X, Wu L, Iliopoulos-Tsoutsouvas C, Wang Y, Wu M, Shen L, Johnston CA, Nikas SP, Song F, Song X, Yuan S, Sun Q, Wu Y, Jiang S, Grim TW, Benchama O, Stahl EL, Zvonok N, Zhao S, Bohn LM, Makriyannis A, Liu ZJ. Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures. Cell. 2020 Jan 28. pii: S0092-8674(20)30055-6. doi: 10.1016/j.cell.2020.01.008. PMID:32004463 doi:http://dx.doi.org/10.1016/j.cell.2020.01.008
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