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Trends Pharmacol Sci. 2018 Jan;39(1):75-89. doi: 10.1016/j.tips.2017.11.001. Epub 2017 Dec 5.

Structural Mapping of Adenosine Receptor Mutations: Ligand Binding and Signaling Mechanisms.

Author information

1
Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, SE-751 24, Uppsala, Sweden; Drug Discovery and Safety, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2333 CC, Leiden, The Netherlands; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
2
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, An der Immenburg 4, 53121 Bonn, Germany.
3
Drug Discovery and Safety, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
4
Heptares Therapeutics, Biopark, Broadwater Road, Welwyn Garden City, Hertfordshire, UK.
5
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
6
Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782. Santiago de Compostela, Spain.
7
Department of Cell and Molecular Biology, Uppsala University, Biomedical Center, Box 596, SE-751 24, Uppsala, Sweden. Electronic address: hugo.gutierrez@icm.uu.se.

Abstract

The four adenosine receptors (ARs), A1, A2A, A2B, and A3, constitute a subfamily of G protein-coupled receptors (GPCRs) with exceptional foundations for structure-based ligand design. The vast amount of mutagenesis data, accumulated in the literature since the 1990s, has been recently supplemented with structural information, currently consisting of several inactive and active structures of the A2A and inactive conformations of the A1 ARs. We provide the first integrated view of the pharmacological, biochemical, and structural data available for this receptor family, by mapping onto the relevant crystal structures all site-directed mutagenesis data, curated and deposited at the GPCR database (available through http://www.gpcrdb.org). This analysis provides novel insights into ligand binding, allosteric modulation, and signaling of the AR family.

KEYWORDS:

G protein-coupled receptor; adenosine receptor; chemical modulation; mutagenesis

PMID:
29203139
DOI:
10.1016/j.tips.2017.11.001
[Indexed for MEDLINE]

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