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The Receptor Concept in 3D: From Hypothesis and Metaphor to GPCR–Ligand Structures

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Abstract

The first mentioning of the word “receptor” for the structure with which a bioactive compound should react for obtaining its specific influence on a physiological system goes back to the years around 1900. The receptor concept was adapted from the lock and key theory for the enzyme substrate and blockers interactions. Through the years the concept, in the beginning rather being a metaphor, not a model, was refined and became reality in recent years. Not only the structures of receptors were elucidated, also the receptor machineries were unraveled. Following a brief historical review we will describe how the recent breakthroughs in the experimental determination of G protein-coupled receptor (GPCR) crystal structures can be complemented by computational modeling, medicinal chemistry, biochemical, and molecular pharmacological studies to obtain new insights into the molecular determinants of GPCR–ligand binding and activation. We will furthermore discuss how this information can be used for structure-based discovery of novel GPCR ligands that bind specific (allosteric) binding sites with desired effects on GPCR functional activity.

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Acknowledgments

With this contribution to this special issue, the Division Medicinal Chemistry of the VU University Amsterdam honors Professor Povl Krogsgaard Larsen. The authors would like to thank all members of the Medicinal Chemistry group of the VU University Amsterdam who have contributed to the histamine receptor research described in this article. A.J.K. and C.d.G. participate in the European Cooperation in Science and Technology Action CM1207 [GPCR–Ligand Interactions, Structures, and Transmembrane Signalling: A European Research Network (GLISTEN)].

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  1. Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands

    Albert J. Kooistra, Chris de Graaf & Henk Timmerman

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  1. Albert J. Kooistra
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  2. Chris de Graaf
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  3. Henk Timmerman
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Correspondence to Chris de Graaf.

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Kooistra, A.J., de Graaf, C. & Timmerman, H. The Receptor Concept in 3D: From Hypothesis and Metaphor to GPCR–Ligand Structures. Neurochem Res 39, 1850–1861 (2014). https://doi.org/10.1007/s11064-014-1398-8

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  • DOI: https://doi.org/10.1007/s11064-014-1398-8

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