title: Oxysterols act as promiscuous ligands of class-A GPCRs: in silico molecular modeling and in vitro validation.
abstract: According to classical pharmacology, each neurotransmitter/hormonal receptor, including GPCRs, is exclusively activated by highly specific ligands. However, recent evidence challenges this dogma. Oxysterols are produced at inflammatory sites and can surprisingly potently activate the Epstein Barr virus induced gene receptor-2 (EBI2), a GPCR involved in adaptive immune responses. Similarly, oxysterols promiscuously operate CXCR2, a chemokine receptor participating to immune reactions and cancer development. Both EBI2 and CXCR2 are phylogenetically related to GPR17, another GPCR implicated in inflammatory/immune neurodegenerative events. Here, we used an integrated approach combining comparative modeling, molecular docking and in vitro experiments to investigate their potential interactions with oxysterols. All three receptors share the binding site to allocate oxysterols with different local arrangements, higher sensitivity to specific oxysterols and different activation thresholds. Such differences may dictate the diverse biological effects induced by oxysterols, depending on production site, concentration, specific spatiotemporal features and receptor expression on targeted cells. Thus, EBI2, CXCR2 and GPR17 are promiscuously operated by oxysterols making this class of ligands a 'fil rouge' linking oxidative stress, inflammation and neurodegeneration. Such a transversal role may represent a conserved, "unspecific" (but selective) signaling mode, by which emergency molecules activate multiple receptors involved in inflammatory/immune responses.
authors.affiliation: Laboratorio di Biochimica e Biofisica Computazionale, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sensi
authors.affiliation: Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università degli Studi di Pisa, Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Daniele
authors.affiliation: Laboratorio di Farmacologia Molecolare e Cellulare della Trasmissione Purinergica, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Parravicini
authors.affiliation: Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università degli Studi di Pisa, Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Zappelli
authors.affiliation: Cancer Gene Therapy Unit, Program of Immunology and Bio Immuno Gene Therapy of Cancer, Division of Molecular Oncology Scientific, Institute San Raffaele, Milan, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Russo
authors.affiliation: Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università degli Studi di Pisa, Pisa, Italy.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Trincavelli
authors.affiliation: Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università degli Studi di Pisa, Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.affiliation: Laboratorio di Farmacologia Molecolare e Cellulare della Trasmissione Purinergica, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Abbracchio
authors.affiliation: Laboratorio di Biochimica e Biofisica Computazionale, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy.
authors.forename: Ivano
authors.initials: I
authors.lastname: Eberini
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D019636:Neurodegenerative Diseases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: C121670:GPR17 protein, human; C080105:GPR183 protein, human; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D023063:Receptors, Interleukin-8B
keywords: Cell signaling; Cholesterol; G proteins; Molecular recognition; Oxysterols; Receptors/seven transmembrane domain