A Cannabinoid Receptor 1 (CB1) binding site for the selective allosteric modulator ORG27569 is here identified through an integrate approach of consensus pocket prediction, mutagenesis studies and Mass Spectrometry. This unprecedented ORG27569 pocket presents the structural features of a Cholesterol Consensus Motif, a cholesterol interacting region already found in other GPCRs. ORG27569 and cholesterol affects oppositely CB1 affinity for orthosteric ligands. Moreover, the rise in cholesterol intracellular level results in CB1 trafficking to the axonal region of neuronal cells, while, on the contrary, ORG27568 binding induces CB1 enrichment at the soma. This control of receptor migration among functionally different membrane regions of the cell further contributes to downstream signalling and adds a previously unknown mechanism underpinning CB1 modulation by ORG27569, that goes beyond a mere control of receptor affinity for orthosteric ligands.

Stornaiuolo, M., Bruno, A., Botta, L., Regina, G.l., Cosconati, S., Silvestri, R., et al. (2015). Endogenous vs Exogenous Allosteric Modulators in GPCRs: A dispute for shuttling CB1 among different membrane microenvironments. SCIENTIFIC REPORTS, 5(1), 15453 [10.1038/srep15453].

Endogenous vs Exogenous Allosteric Modulators in GPCRs: A dispute for shuttling CB1 among different membrane microenvironments

Botta L.;
2015-01-01

Abstract

A Cannabinoid Receptor 1 (CB1) binding site for the selective allosteric modulator ORG27569 is here identified through an integrate approach of consensus pocket prediction, mutagenesis studies and Mass Spectrometry. This unprecedented ORG27569 pocket presents the structural features of a Cholesterol Consensus Motif, a cholesterol interacting region already found in other GPCRs. ORG27569 and cholesterol affects oppositely CB1 affinity for orthosteric ligands. Moreover, the rise in cholesterol intracellular level results in CB1 trafficking to the axonal region of neuronal cells, while, on the contrary, ORG27568 binding induces CB1 enrichment at the soma. This control of receptor migration among functionally different membrane regions of the cell further contributes to downstream signalling and adds a previously unknown mechanism underpinning CB1 modulation by ORG27569, that goes beyond a mere control of receptor affinity for orthosteric ligands.
2015
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore CHIM/06 - CHIMICA ORGANICA
English
Allosteric Regulation; Axons; Binding Sites; Cell Line; Cell Membrane; Cholesterol; Humans; Indoles; Intracellular Space; Models, Molecular; Molecular Conformation; Mutation; Neurons; Piperidines; Protein Binding; Protein Transport; Receptor, Cannabinoid, CB1; Receptors, G-Protein-Coupled; Ligands; Structure-Activity Relationship
Stornaiuolo, M., Bruno, A., Botta, L., Regina, G.l., Cosconati, S., Silvestri, R., et al. (2015). Endogenous vs Exogenous Allosteric Modulators in GPCRs: A dispute for shuttling CB1 among different membrane microenvironments. SCIENTIFIC REPORTS, 5(1), 15453 [10.1038/srep15453].
Stornaiuolo, M; Bruno, A; Botta, L; Regina, Gl; Cosconati, S; Silvestri, R; Marinelli, L; Novellino, E
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/273545
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