title: Probing the Binding Site of Bile Acids in TGR5.
abstract: TGR5 is a G-protein-coupled receptor (GPCR) mediating cellular responses to bile acids (BAs). Although some efforts have been devoted to generate homology models of TGR5 and draw structure-activity relationships of BAs, none of these studies has hitherto described how BAs bind to TGR5. Here, we present an integrated computational, chemical, and biological approach that has been instrumental to determine the binding mode of BAs to TGR5. As a result, key residues have been identified that are involved in mediating the binding of BAs to the receptor. Collectively, these results provide new hints to design potent and selective TGR5 agonists.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia , 06123 Perugia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia , 06123 Perugia, Italy.
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello
authors.affiliation: Laboratory of Integrative and Systems Physiology (LISP), Ecole Polytechnique Fédérale de Lausanne (EPFL) , CH 1015 Lausanne, Switzerland.
authors.forename: Charles
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Laboratory of Integrative and Systems Physiology (LISP), Ecole Polytechnique Fédérale de Lausanne (EPFL) , CH 1015 Lausanne, Switzerland.
authors.forename: Thijs W H
authors.initials: TW
authors.lastname: Pols
authors.affiliation: TES Pharma S.r.l. , via Palmiro Togliatti 20, 06073 Corciano (Perugia), Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Nuti
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia , 06123 Perugia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ferrari
authors.affiliation: TES Pharma S.r.l. , via Palmiro Togliatti 20, 06073 Corciano (Perugia), Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Giacchè
authors.affiliation: TES Pharma S.r.l. , via Palmiro Togliatti 20, 06073 Corciano (Perugia), Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Franco
authors.affiliation: Intercept Pharmaceuticals , 18 Desbrosses Street, New York, New York 10013, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Pruzanski
authors.affiliation: Laboratory of Integrative and Systems Physiology (LISP), Ecole Polytechnique Fédérale de Lausanne (EPFL) , CH 1015 Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Laboratory of Integrative and Systems Physiology (LISP), Ecole Polytechnique Fédérale de Lausanne (EPFL) , CH 1015 Lausanne, Switzerland.
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia , 06123 Perugia, Italy ; TES Pharma S.r.l. , via Palmiro Togliatti 20, 06073 Corciano (Perugia), Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
keywords: Bile acids; GPCR; TGR5; diabetes; homology modeling; molecular docking; site-directed mutagenesis