Abstract
The crystal structure of the human histamine H1 receptor (H1R) has been determined in complex with its inverse agonist doxepin, a first-generation antihistamine. The crystal structure showed that doxepin sits deeply inside the ligand-binding pocket and predominantly interacts with residues highly conserved among other aminergic receptors. This binding mode is considered to result in the low selectivity of the first-generation antihistamines for H1R. The crystal structure also revealed the mechanism of receptor inactivation by the inverse agonist doxepin. On the other hand, the crystal structure elucidated the anion-binding site near the extracellular portion of the receptor. This site consists of residues not conserved among other aminergic receptors, which are specific for H1R. Docking simulation and biochemical experimentation demonstrated that a carboxyl group on the second-generation antihistamines interacts with the anion-binding site. These results imply that the anion-binding site is a key site for the development of highly selective antihistamine drugs.
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References
Bakker RA, Wieland K, Timmerman H et al (2000) Constitutive activity of the histamine H1 receptor reveals inverse agonism of histamine H1 receptor antagonists. Eur J Pharmacol 387:R5–R7. doi:10.1016/S0014-2999(99)00803-1
Bruysters M, Pertz HH, Teunissen A et al (2004) Mutational analysis of the histamine H1-receptor binding pocket of histaprodifens. Eur J Pharmacol 487:55–63. doi:10.1016/j.ejphar.2004.01.028
Cherezov V, Rosenbaum DM, Hanson MA et al (2007) High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318:1258–1265
Chien EY, Liu W, Zhao Q et al (2010) Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330:1091–1095. doi:10.1126/science.1197410
Cusack B, Nelson A, Richelson E (1994) Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl) 114:559–565
de Graaf C, Kooistra AJ, Vischer HF et al (2011) Crystal structure-based virtual screening for fragment-like ligands of the human histamine H1 receptor. J Med Chem 54:8195–8206. doi:10.1021/jm2011589
Hanson MA, Cherezov V, Griffith MT et al (2008) A specific cholesterol binding site is established by the 2.8 Å structure of the human β2-adrenergic receptor. Structure 16:897–905. doi:10.1016/j.str.2008.05.001
Hill SJ (1990) Distribution, properties, and functional characteristics of three classes of histamine receptor. Pharmacol Rev 42:45–83
Hill SJ, Ganellin CR, Timmerman H et al (1997) International union of pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev 49:253–278
Jaakola VP, Griffith MT, Hanson MA et al (2008) The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist. Science 322:1211–1217. doi:10.1126/science.1164772
Jongejan A, Bruysters M, Ballesteros JA et al (2005) Linking agonist binding to histamine H1 receptor activation. Nat Chem Biol 1:98–103. doi:10.1038/nchembio714
Nonaka H, Otaki S, Ohshima E et al (1998) Unique binding pocket for KW-4679 in the histamine H1 receptor. Eur J Pharmacol 345:111–117
Ohta K, Hayashi H, Mizuguchi H (1994) Site-directed mutagenesis of the histamine H1 receptor: roles of aspartic acid107, asparagine198 and threonine194. Biochem Biophys Res Commun 203:1096–1101. doi:10.1006/bbrc.1994.2295
Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5:993–996. doi:10.1038/nrd2199
Palczewski K, Kumasaka T, Hori T et al (2000) Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289:739–745
Rosenbaum DM, Cherezov V, Hanson MA et al (2007) GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science 318:1266–1273
Schwartz JC, Arrang JM, Garbarg M et al (1991) Histaminergic transmission in the mammalian brain. Physiol Rev 71:1–51
Shimamura T, Shiroishi M, Weyand S et al (2011) Structure of the human histamine H1 receptor complex with doxepin. Nature 475:65–70. doi:10.1038/nature10236
Shiroishi M, Kobayashi T, Ogasawara S et al (2011) Production of the stable human histamine H(1) receptor in Pichia pastoris for structural determination. Methods. doi:10.1016/j.ymeth.2011.08.015
Shiroishi M, Tsujimoto H, Makyio H et al (2012) Platform for the rapid construction and evaluation of GPCRs for crystallography in Saccharomyces cerevisiae. Microb Cell Fact 11:78. doi:10.1186/1475-2859-11-78
Sun X, Agren H, Tu Y (2014) Functional water molecules in rhodopsin activation. J Phys Chem B 118:10863–10873. doi:10.1021/jp505180t
Tashiro M, Kato M, Miyake M et al (2009) Dose dependency of brain histamine H1 receptor occupancy following oral administration of cetirizine hydrochloride measured using PET with [11C]doxepin. Hum Psychopharmacol 24:540–548. doi:10.1002/hup.1051
Tehan BG, Bortolato A, Blaney FE et al (2014) Unifying family A GPCR theories of activation. Pharmacol Ther 143:51–60. doi:10.1016/j.pharmthera.2014.02.004
Warne T, Serrano-Vega MJ, Baker JG et al (2008) Structure of a beta1-adrenergic G-protein-coupled receptor. Nature 454:486–491. doi:10.1038/nature07101
Wieland K, Laak AM, Smit MJ et al (1999) Mutational analysis of the antagonist-binding site of the histamine H1 receptor. J Biol Chem 274:29994–30000
Woosley RL, Chen Y, Freiman JP et al (1993) Mechanism of the cardiotoxic actions of terfenadine. JAMA 269:1532–1536
Wu B, Chien EY, Mol CD et al (2010) Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 330:1066–1071. doi:10.1126/science.1194396
Yamashita M, Fukui H, Sugama K et al (1991) Expression cloning of a cDNA encoding the bovine histamine H1 receptor. Proc Natl Acad Sci U S A 88:11515–11519
Yap YG, Gamm AJ (2002) Potential cardiac toxicity of H1-antihistamines. Clin Allergy Immunol 17:389–419
Acknowledgments
This work was supported by the ERATO IWATA Human Receptor Crystallography Project from the Japan Science and Technology Agency, the Targeted Proteins Research Program of MEXT, the Mochida Memorial Foundation for Medical and Pharmaceutical Research (T. K.), Takeda Scientific Foundation (M. S. and T. K.), and the Sumitomo Foundation (T. K.).
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Shiroishi, M., Kobayashi, T. (2016). Structural Analysis of the Histamine H1 Receptor. In: Hattori, Y., Seifert, R. (eds) Histamine and Histamine Receptors in Health and Disease. Handbook of Experimental Pharmacology, vol 241. Springer, Cham. https://doi.org/10.1007/164_2016_10
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DOI: https://doi.org/10.1007/164_2016_10
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