| Structural highlights
Function
FLAV_DESVH Low-potential electron donor to a number of redox enzymes.CNR1_HUMAN Involved in cannabinoid-induced CNS effects. Acts by inhibiting adenylate cyclase. Could be a receptor for anandamide. Inhibits L-type Ca(2+) channel current. Isoform 2 and isoform 3 have altered ligand binding.[1]
Publication Abstract from PubMed
Due to the lack of genetically encoded probes for fluorine-19 nuclear magnetic resonance spectroscopy ((19)F NMR), its utility for probing eukaryotic membrane protein dynamics is limited. Here we report an efficient method for the genetic incorporation of an unnatural amino acid (UAA), 3'-trifluoromenthyl-phenylalanine (mtfF), into cannabinoid receptor 1 (CB1) in the Baculovirus Expression System. The probe can be inserted at any environmentally sensitive site, while causing minimal structural perturbation to the target protein. Using (19)F NMR and X-ray crystallography methods, we discovered that the allosteric modulator Org27569 and agonists synergistically stabilize a previously unrecognized pre-active state. An allosteric modulation model is proposed to explain Org27569's distinct behavior. We demonstrate that our site-specific (19)F NMR labeling method is a powerful tool in decoding the mechanism of GPCR allosteric modulation. This new method should be broadly applicable for uncovering conformational states for many important eukaryotic membrane proteins.
A Genetically Encoded F-19 NMR Probe Reveals the Allosteric Modulation Mechanism of Cannabinoid Receptor 1.,Wang X, Liu D, Shen L, Li F, Li Y, Yang L, Xu T, Tao H, Yao D, Wu L, Hirata K, Bohn LM, Makriyannis A, Liu X, Hua T, Liu ZJ, Wang J J Am Chem Soc. 2021 Oct 13;143(40):16320-16325. doi: 10.1021/jacs.1c06847. Epub, 2021 Oct 1. PMID:34596399[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ryberg E, Vu HK, Larsson N, Groblewski T, Hjorth S, Elebring T, Sjogren S, Greasley PJ. Identification and characterisation of a novel splice variant of the human CB1 receptor. FEBS Lett. 2005 Jan 3;579(1):259-64. PMID:15620723 doi:http://dx.doi.org/10.1016/j.febslet.2004.11.085
- ↑ Wang X, Liu D, Shen L, Li F, Li Y, Yang L, Xu T, Tao H, Yao D, Wu L, Hirata K, Bohn LM, Makriyannis A, Liu X, Hua T, Liu ZJ, Wang J. A Genetically Encoded F-19 NMR Probe Reveals the Allosteric Modulation Mechanism of Cannabinoid Receptor 1. J Am Chem Soc. 2021 Oct 13;143(40):16320-16325. PMID:34596399 doi:10.1021/jacs.1c06847
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