Covalent agonists for studying G protein-coupled receptor activation

78Citations
Citations of this article
182Readers
Mendeley users who have this article in their library.

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.

References Powered by Scopus

Processing of X-ray diffraction data collected in oscillation mode

39316Citations
N/AReaders
Get full text

Coot: Model-building tools for molecular graphics

26130Citations
N/AReaders
Get full text

Phaser crystallographic software

16599Citations
N/AReaders
Get full text

Cited by Powered by Scopus

Structure-based discovery of opioid analgesics with reduced side effects

742Citations
N/AReaders
Get full text

Methodological advances: The unsung heroes of the GPCR structural revolution

168Citations
N/AReaders
Get full text

GPCR crystal structures: Medicinal chemistry in the pocket

100Citations
N/AReaders
Get full text

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Cite

CITATION STYLE

APA

Weichert, D., Kruse, A. C., Manglik, A., Hiller, C., Zhang, C., Hub̈ner, 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(29), 10744–10748. https://doi.org/10.1073/pnas.1410415111

Readers over time

‘14‘15‘16‘17‘18‘19‘20‘21‘22‘23‘24‘2507142128

Readers' Seniority

Tooltip

PhD / Post grad / Masters / Doc 81

68%

Researcher 31

26%

Professor / Associate Prof. 7

6%

Readers' Discipline

Tooltip

Biochemistry, Genetics and Molecular Bi... 37

30%

Agricultural and Biological Sciences 36

30%

Chemistry 27

22%

Pharmacology, Toxicology and Pharmaceut... 22

18%

Article Metrics

Tooltip
Mentions
References: 1
Social Media
Shares, Likes & Comments: 30

Save time finding and organizing research with Mendeley

Sign up for free
0