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Linking agonist binding to histamine H1 receptor activation

Nature Chemical Biology volume 1, pages 98–103 (2005)Cite this article

Abstract

G protein–coupled receptors (GPCRs) constitute a large and functionally diverse family of transmembrane proteins. They are fundamental in the transfer of extracellular stimuli to intracellular signaling pathways and are among the most targeted proteins in drug discovery. The detailed molecular mechanism for agonist-induced activation of rhodopsin-like GPCRs has not yet been described. Using a combination of site-directed mutagenesis and molecular modeling, we characterized important steps in the activation of the human histamine H1 receptor. Both Ser3.36 and Asn7.45 are important links between histamine binding and previously proposed conformational changes in helices 6 and 7. Ser3.36 acts as a rotamer toggle switch that, upon agonist binding, initiates the activation of the receptor through Asn7.45. The proposed transduction involves specific residues that are conserved among rhodopsin-like GPCRs.

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Figure 1: Modeling of the human H1R.
Figure 2: Characterization of wild-type (WT) and Ser3.36 mutant H1Rs.
Figure 3: Characterization of wild-type (WT) and Asn7.45 mutant H1Rs.
Figure 4: Proposed model of H1R activation.

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Acknowledgements

The authors wish to thank J. Springer for sharing his experimental results. UCB Pharma and the National Institute of Mental Health (grant R01MH068655-01A1) are gratefully acknowledged for their financial support of our H1R research. We thank the European Community (LSHB-CT-2003-503337) and Ministerio de Ciencia y Technología (SAF2002-01509) for financial support.

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Author notes

  1. Aldo Jongejan, Martijn Bruysters and Leonardo Pardo: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1083, Amsterdam, 1081 HV, The Netherlands

    Aldo Jongejan, Martijn Bruysters, Remko A Bakker & Rob Leurs

  2. Novasite Pharmaceuticals Inc., 11095 Flintkote Avenue, San Diego, 92121, California, USA

    Juan A Ballesteros

  3. Dept. of Medicinal Chemistry, Boehringer Ingelheim Austria GmbH, Dr. Boehringergasse 5-11, Vienna, 1121, Austria

    Eric Haaksma

  4. Laboratori de Medicina Computacional, Unitat de Bioestadística and Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain

    Leonardo Pardo

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  1. Aldo Jongejan
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Correspondence to Rob Leurs.

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Supplementary information

Supplementary Table 1

Affinities and expression levels of WT and several human H1R mutants. (PDF 108 kb)

Supplementary Table 2

Cross-reference table for amino acids described in the manuscript. (PDF 65 kb)

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Jongejan, A., Bruysters, M., Ballesteros, J. et al. Linking agonist binding to histamine H1 receptor activation. Nat Chem Biol 1, 98–103 (2005). https://doi.org/10.1038/nchembio714

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