title: A cell-permeable inhibitor to trap Gαq proteins in the empty pocket conformation.
abstract: In spite of the crucial role of heterotrimeric G proteins as molecular switches transmitting signals from G protein-coupled receptors, their selective manipulation with small molecule, cell-permeable inhibitors still remains an unmet challenge. Here, we report that the small molecule BIM-46187, previously classified as pan-G protein inhibitor, preferentially silences Gαq signaling in a cellular context-dependent manner. Investigations into its mode of action reveal that BIM traps Gαq in the empty pocket conformation by permitting GDP exit but interdicting GTP entry, a molecular mechanism not yet assigned to any other small molecule Gα inhibitor to date. Our data show that Gα proteins may be "frozen" pharmacologically in an intermediate conformation along their activation pathway and propose a pharmacological strategy to specifically silence Gα subclasses with cell-permeable inhibitors.
authors.affiliation: Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Schmitz
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Schrage
authors.affiliation: Department of Dermatology and Allergy, Laboratory of Experimental Dermatology, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Gaffal
authors.affiliation: Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7365, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Charpentier
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Wiest
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Hiltensperger
authors.affiliation: Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Morschel
authors.affiliation: Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hennen
authors.affiliation: Pharmaceutical Chemistry I, Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Häußler
authors.affiliation: Eduard-Zintl-Institute of Inorganic and Physical Chemistry, Technische Universität Darmstadt, Alarich-Weiss-Straße 8, 64287 Darmstadt, Germany.
authors.forename: Velten
authors.initials: V
authors.lastname: Horn
authors.affiliation: Institute of Physiology I, Life and Brain Center, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wenzel
authors.affiliation: Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Grundmann
authors.affiliation: Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany.
authors.forename: Katrin M
authors.initials: KM
authors.lastname: Büllesbach
authors.affiliation: Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Schröder
authors.affiliation: Pharmaceutical Chemistry I, Institute of Pharmacy, University of Bonn, Brühler Straße 7, 53119 Bonn, Germany.
authors.forename: H Henning
authors.initials: HH
authors.lastname: Brewitz
authors.affiliation: Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany.
authors.forename: Jesús
authors.initials: J
authors.lastname: Gomeza
authors.affiliation: Institut des Maladies Métaboliques et Cardiovasculaires, Institut Nataional de la Santé et de la Recherche Médicale, Université Toulouse III Paul Sabatier, 31432 Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Galés
authors.affiliation: Institute of Physiology I, Life and Brain Center, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany.
authors.forename: Bernd K
authors.initials: BK
authors.lastname: Fleischmann
authors.affiliation: Department of Dermatology and Allergy, Laboratory of Experimental Dermatology, University of Bonn, Sigmund-Freud-Straße 25, 53105 Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
authors.affiliation: Pharmaceutical Chemistry I, Institute of Pharmacy, University of Bonn, Brühler Straße 7, 53119 Bonn, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Imhof
authors.affiliation: Eduard-Zintl-Institute of Inorganic and Physical Chemistry, Technische Universität Darmstadt, Alarich-Weiss-Straße 8, 64287 Darmstadt, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tietze
authors.affiliation: Pharmaceutical Chemistry I, Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.affiliation: Department of Pharmacology and Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7365, United States.
authors.forename: John
authors.initials: J
authors.lastname: Sondek
authors.affiliation: Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7365, USA.
authors.forename: T Kendall
authors.initials: TK
authors.lastname: Harden
authors.affiliation: Pharmacology and Toxicology Section, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Mohr
authors.affiliation: Molecular, Cellular, and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany. Electronic address: kostenis@uni-bonn.de.
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003510:Cyclohexanes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D019281:Dimerization; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010539:Permeability; D011487:Protein Conformation / Q000187:drug effects; D011719:Pyrazines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C533004:7-(2-amino-1-oxo-3-thio-propyl)-8-cyclohexylmethyl-2-phenyl-5,6,7,8-tetrahydro-imidazo-(1,2a)-pyrazine dimer, hydrochloride; D003510:Cyclohexanes; D011719:Pyrazines; D043802:GTP-Binding Protein alpha Subunits, Gq-G11