Covalent agonists for studying G protein-coupled receptor activation

Weichert D, Kruse AC, Manglik A, Hiller C, Zhang C, Hübner H, Kobilka BK, Gmeiner P (2014)

Publication Language: English

Publication Type: Journal article, Original article

Publication year: 2014

Journal

Publisher: National Academy of Sciences

Book Volume: 111

Pages Range: 10744-10748

DOI: 10.1073/pnas.1410415111

Abstract

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.

Authors with CRIS profile

Additional Organisation(s)

Involved external institutions

Stanford University United States (USA) (US)

How to cite

APA:

Weichert, D., Kruse, A.C., Manglik, A., Hiller, C., Zhang, C., Hübner, H.,... Gmeiner, P. (2014). Covalent agonists for studying G protein-coupled receptor activation. Proceedings of the National Academy of Sciences of the United States of America, 111, 10744-10748. https://dx.doi.org/10.1073/pnas.1410415111

MLA:

Weichert, Dietmar, et al. "Covalent agonists for studying G protein-coupled receptor activation." Proceedings of the National Academy of Sciences of the United States of America 111 (2014): 10744-10748.

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