Covalent agonists for studying G protein-coupled receptor activation. 2014

Dietmar Weichert, and Andrew C Kruse, and Aashish Manglik, and Christine Hiller, and Cheng Zhang, and Harald Hübner, and Brian K Kobilka, and Peter Gmeiner
Department of Chemistry and Pharmacy, Friedrich Alexander University, 91052 Erlangen, Germany; and.

Structural studies on G protein-coupled receptors (GPCRs) provide important insights into the architecture and function of these important drug targets. However, the crystallization of GPCRs in active states is particularly challenging, requiring the formation of stable and conformationally homogeneous ligand-receptor complexes. Native hormones, neurotransmitters, and synthetic agonists that bind with low affinity are ineffective at stabilizing an active state for crystallogenesis. To promote structural studies on the pharmacologically highly relevant class of aminergic GPCRs, we here present the development of covalently binding molecular tools activating Gs-, Gi-, and Gq-coupled receptors. The covalent agonists are derived from the monoamine neurotransmitters noradrenaline, dopamine, serotonin, and histamine, and they were accessed using a general and versatile synthetic strategy. We demonstrate that the tool compounds presented herein display an efficient covalent binding mode and that the respective covalent ligand-receptor complexes activate G proteins comparable to the natural neurotransmitters. A crystal structure of the β2-adrenoreceptor in complex with a covalent noradrenaline analog and a conformationally selective antibody (nanobody) verified that these agonists can be used to facilitate crystallogenesis.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D009638 Norepinephrine Precursor of epinephrine that is secreted by the ADRENAL MEDULLA and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the LOCUS CERULEUS. It is also found in plants and is used pharmacologically as a sympathomimetic. Levarterenol,Levonorepinephrine,Noradrenaline,Arterenol,Levonor,Levophed,Levophed Bitartrate,Noradrenaline Bitartrate,Noradrénaline tartrate renaudin,Norepinephrin d-Tartrate (1:1),Norepinephrine Bitartrate,Norepinephrine Hydrochloride,Norepinephrine Hydrochloride, (+)-Isomer,Norepinephrine Hydrochloride, (+,-)-Isomer,Norepinephrine d-Tartrate (1:1),Norepinephrine l-Tartrate (1:1),Norepinephrine l-Tartrate (1:1), (+,-)-Isomer,Norepinephrine l-Tartrate (1:1), Monohydrate,Norepinephrine l-Tartrate (1:1), Monohydrate, (+)-Isomer,Norepinephrine l-Tartrate (1:2),Norepinephrine l-Tartrate, (+)-Isomer,Norepinephrine, (+)-Isomer,Norepinephrine, (+,-)-Isomer
D011869 Radioligand Assay Quantitative determination of receptor (binding) proteins in body fluids or tissue using radioactively labeled binding reagents (e.g., antibodies, intracellular receptors, plasma binders). Protein-Binding Radioassay,Radioreceptor Assay,Assay, Radioligand,Assay, Radioreceptor,Assays, Radioligand,Assays, Radioreceptor,Protein Binding Radioassay,Protein-Binding Radioassays,Radioassay, Protein-Binding,Radioassays, Protein-Binding,Radioligand Assays,Radioreceptor Assays
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D058666 Adrenergic beta-2 Receptor Agonists Compounds bind to and activate ADRENERGIC BETA-2 RECEPTORS. Adrenergic beta-2 Agonists,Adrenergic beta-2 Receptor Agonist,Adrenergic beta2-Agonists,Adrenergic beta 2 Agonists,Adrenergic beta 2 Receptor Agonist,Adrenergic beta 2 Receptor Agonists,Adrenergic beta2 Agonists,Agonists, Adrenergic beta-2,beta-2 Agonists, Adrenergic,beta2-Agonists, Adrenergic
D018343 Receptors, Adrenergic, beta-2 A subclass of beta-adrenergic receptors (RECEPTORS, ADRENERGIC, BETA). The adrenergic beta-2 receptors are more sensitive to EPINEPHRINE than to NOREPINEPHRINE and have a high affinity for the agonist TERBUTALINE. They are widespread, with clinically important roles in SKELETAL MUSCLE; LIVER; and vascular, bronchial, gastrointestinal, and genitourinary SMOOTH MUSCLE. Adrenergic beta-2 Receptors,Receptors, beta-2 Adrenergic,beta-2 Adrenergic Receptors,Adrenergic Receptor, beta-2,Receptor, Adrenergic, beta-2,beta 2 Adrenergic Receptors,Adrenergic Receptor, beta 2,Adrenergic Receptors, beta-2,Adrenergic beta 2 Receptors,Receptor, beta-2 Adrenergic,Receptors, Adrenergic beta-2,Receptors, beta 2 Adrenergic,beta-2 Adrenergic Receptor,beta-2 Receptors, Adrenergic
D018377 Neurotransmitter Agents Substances used for their pharmacological actions on any aspect of neurotransmitter systems. Neurotransmitter agents include agonists, antagonists, degradation inhibitors, uptake inhibitors, depleters, precursors, and modulators of receptor function. Nerve Transmitter Substance,Neurohormone,Neurohumor,Neurotransmitter Agent,Nerve Transmitter Substances,Neurohormones,Neurohumors,Neuromodulator,Neuromodulators,Neuroregulator,Neuroregulators,Neurotransmitter,Neurotransmitters,Substances, Nerve Transmitter,Transmitter Substances, Nerve,Substance, Nerve Transmitter,Transmitter Substance, Nerve

Related Publications

Dietmar Weichert, and Andrew C Kruse, and Aashish Manglik, and Christine Hiller, and Cheng Zhang, and Harald Hübner, and Brian K Kobilka, and Peter Gmeiner
January 2010, Methods in molecular biology (Clifton, N.J.),
Dietmar Weichert, and Andrew C Kruse, and Aashish Manglik, and Christine Hiller, and Cheng Zhang, and Harald Hübner, and Brian K Kobilka, and Peter Gmeiner
May 2011, Analytical biochemistry,
Dietmar Weichert, and Andrew C Kruse, and Aashish Manglik, and Christine Hiller, and Cheng Zhang, and Harald Hübner, and Brian K Kobilka, and Peter Gmeiner
June 2015, Journal of receptor and signal transduction research,
Dietmar Weichert, and Andrew C Kruse, and Aashish Manglik, and Christine Hiller, and Cheng Zhang, and Harald Hübner, and Brian K Kobilka, and Peter Gmeiner
January 2007, Metal-based drugs,
Dietmar Weichert, and Andrew C Kruse, and Aashish Manglik, and Christine Hiller, and Cheng Zhang, and Harald Hübner, and Brian K Kobilka, and Peter Gmeiner
July 1999, Trends in pharmacological sciences,
Dietmar Weichert, and Andrew C Kruse, and Aashish Manglik, and Christine Hiller, and Cheng Zhang, and Harald Hübner, and Brian K Kobilka, and Peter Gmeiner
September 2012, Cell,
Dietmar Weichert, and Andrew C Kruse, and Aashish Manglik, and Christine Hiller, and Cheng Zhang, and Harald Hübner, and Brian K Kobilka, and Peter Gmeiner
January 2011, Neuropharmacology,
Dietmar Weichert, and Andrew C Kruse, and Aashish Manglik, and Christine Hiller, and Cheng Zhang, and Harald Hübner, and Brian K Kobilka, and Peter Gmeiner
October 2017, Biochemistry,
Dietmar Weichert, and Andrew C Kruse, and Aashish Manglik, and Christine Hiller, and Cheng Zhang, and Harald Hübner, and Brian K Kobilka, and Peter Gmeiner
August 2006, Nature chemical biology,
Dietmar Weichert, and Andrew C Kruse, and Aashish Manglik, and Christine Hiller, and Cheng Zhang, and Harald Hübner, and Brian K Kobilka, and Peter Gmeiner
June 1999, The American journal of cardiology,
Copied contents to your clipboard!