ArticleJournal of proteome research2011
Mass spectrometry-based proteomics of human cannabinoid receptor 2: covalent cysteine 6.47(257)-ligand interaction affording megagonist receptor activation.
Article in Journal of proteome research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Comparison of Agonist Activity between CB1 and CB2 Receptors with Orthosteric Site Mutations.Receptors (Basel, Switzerland) · 2024Article
- Structural basis of ΔResearch square · 2024Article
- Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years.Pharmacological reviews · 2023Review
- Covalent cannabinoid receptor ligands - structural insight and selectivity challenges.RSC medicinal chemistry · 2022Review
- Functionalized Cannabinoid Subtype 2 Receptor Ligands: Fluorescent, PET, Photochromic and Covalent Molecular Probes.ChemMedChem · 2020Review
- Expression, Purification and Characterization of the Human Cannabinoid 1 Receptor.Scientific reports · 2018Article
- Binding Site Characterization of AM1336, a Novel Covalent Inverse Agonist at Human Cannabinoid 2 Receptor, Using Mass Spectrometric Analysis.Journal of proteome research · 2017Article
- Leveraging allostery to improve G protein-coupled receptor (GPCR)-directed therapeutics: cannabinoid receptor 1 as discovery target.Expert opinion on drug discovery · 2016Review
- Article
- Synthesis and biological evaluation of indole-2-carboxamides bearing photoactivatable functionalities as novel allosteric modulators for the cannabinoid CB1 receptor.European journal of medicinal chemistry · 2016Article
- Mapping Cannabinoid 1 Receptor Allosteric Site(s): Critical Molecular Determinant and Signaling Profile of GAT100, a Novel, Potent, and Irreversibly Binding Probe.ACS chemical neuroscience · 2016Article
- Novel Electrophilic and Photoaffinity Covalent Probes for Mapping the Cannabinoid 1 Receptor Allosteric Site(s).Journal of medicinal chemistry · 2016Article
- In vitro and non-invasive in vivo effects of the cannabinoid-1 receptor agonist AM841 on gastrointestinal motor function in the rat.Neurogastroenterology and motility · 2015Article
- Molecular-interaction and signaling profiles of AM3677, a novel covalent agonist selective for the cannabinoid 1 receptor.ACS chemical neuroscience · 2015Article
- AM841, a covalent cannabinoid ligand, powerfully slows gastrointestinal motility in normal and stressed mice in a peripherally restricted manner.British journal of pharmacology · 2015Article
- 3'-functionalized adamantyl cannabinoid receptor probes.Journal of medicinal chemistry · 2015Article
- Terpenes and lipids of the endocannabinoid and transient-receptor-potential-channel biosignaling systems.ACS chemical neuroscience · 2014Review
- 2012 Division of medicinal chemistry award address. Trekking the cannabinoid road: a personal perspective.Journal of medicinal chemistry · 2014Article
- Cannabinoids alleviate experimentally induced intestinal inflammation by acting at central and peripheral receptors.PloS one · 2014Article
- Design and pharmacological characterization of VUF14480, a covalent partial agonist that interacts with cysteine 98(3.36) of the human histamine H₄ receptor.British journal of pharmacology · 2013Article
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
The lack of experimental characterization of the structures and ligand-binding motifs of therapeutic G-protein coupled receptors (GPCRs) hampers rational drug discovery. The human cannabinoid receptor 2 (hCB2R) is a class-A GPCR and promising therapeutic target for small-molecule cannabinergic agonists as medicines. Prior mutational and modeling data constitute provisional evidence that AM-841, a high-affinity classical cannabinoid, interacts with cysteine C6.47(257) in hCB2R transmembrane helix 6 (TMH6) to afford improved hCB2R selectivity and unprecedented agonist potency. We now apply bottom-up mass spectrometry (MS)-based proteomics to define directly the hCB2R-AM-841 interaction at the amino-acid level. Recombinant hCB2R, overexpressed as an N-terminal FLAG-tagged/C-terminal 6His-tagged protein (FLAG-hCB2R-6His) with a baculovirus system, was solubilized and purified by immunochromatography as functional receptor. A multiplex multiple reaction monitoring (MRM)-MS method was developed that allowed us to observe unambiguously all seven discrete TMH peptides in the tryptic digest of purified FLAG-hCB2R-6His and demonstrate that AM-841 modifies hCB2R TMH6 exclusively. High-resolution mass spectra of the TMH6 tryptic peptide obtained by Q-TOF MS/MS analysis demonstrated that AM-841 covalently and selectively modifies hCB2R at TMH6 cysteine C6.47(257). These data demonstrate how integration of MS-based proteomics into a ligand-assisted protein structure (LAPS) experimental paradigm can offer guidance to structure-enabled GPCR agonist design.
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