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Research ArticleArticle

Molecular Modeling and Site-Specific Mutagenesis of the Histamine-Binding Site of the Histamine H4 Receptor

Niu Shin, Elizabeth Coates, Nicholas J. Murgolo, Kelley L. Morse, Marvin Bayne, Catherine D. Strader and Frederick J. Monsma Jr.
Molecular Pharmacology July 2002, 62 (1) 38-47; DOI: https://doi.org/10.1124/mol.62.1.38
Niu Shin
Discovery Technologies Department, Schering-Plough Research Institute, Kenilworth, New Jersey
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Elizabeth Coates
Discovery Technologies Department, Schering-Plough Research Institute, Kenilworth, New Jersey
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Nicholas J. Murgolo
Discovery Technologies Department, Schering-Plough Research Institute, Kenilworth, New Jersey
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Kelley L. Morse
Discovery Technologies Department, Schering-Plough Research Institute, Kenilworth, New Jersey
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Marvin Bayne
Discovery Technologies Department, Schering-Plough Research Institute, Kenilworth, New Jersey
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Catherine D. Strader
Discovery Technologies Department, Schering-Plough Research Institute, Kenilworth, New Jersey
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Frederick J. Monsma Jr.
Discovery Technologies Department, Schering-Plough Research Institute, Kenilworth, New Jersey
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Abstract

The histamine H4 receptor is a novel G-protein–coupled receptor with a unique pharmacological profile. The distribution of H4 mRNA suggests that it may play a role in the regulation of immune function, particularly with respect to allergy and asthma. To define the histamine-binding site of this receptor, molecular modeling and site-directed mutagenesis were used to predict and alter amino acids residing in the histamine-binding pocket. The effects of these alterations on histamine binding and receptor activation were then assessed. Our results indicate that Asp94 (3.32) in transmembrane region (TM) 3 and Glu182 (5.46) in TM5 are critically involved in histamine binding. Asp94probably serves as a counter-anion to the cationic amino group of histamine, whereas Glu182 (5.46) interacts with the Nτ nitrogen atom of the histamine imidazole ring via an ion pair. In contrast, Thr178 (5.42) and Ser179(5.43) in TM5 are not significantly involved in either histamine binding or receptor activation. These results resemble those for the analogous residues in the H1 histamine receptor but contrast with findings regarding the H2 histamine receptor. Our results also demonstrate that Asn147 (4.57) in TM4 and Ser320 (6.52) in TM6 play a role in receptor activation but are not involved in histamine binding. Taken together, these data indicate that although histamine seems to bind to the H4receptor in a fashion similar to that predicted for the other histamine receptor subtypes, there are also important differences that can probably be exploited for the discovery of novel H4-selective compounds.

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Molecular Pharmacology: 62 (1)
Molecular Pharmacology
Vol. 62, Issue 1
1 Jul 2002
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Research ArticleArticle

Molecular Modeling and Site-Specific Mutagenesis of the Histamine-Binding Site of the Histamine H4 Receptor

Niu Shin, Elizabeth Coates, Nicholas J. Murgolo, Kelley L. Morse, Marvin Bayne, Catherine D. Strader and Frederick J. Monsma
Molecular Pharmacology July 1, 2002, 62 (1) 38-47; DOI: https://doi.org/10.1124/mol.62.1.38

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Research ArticleArticle

Molecular Modeling and Site-Specific Mutagenesis of the Histamine-Binding Site of the Histamine H4 Receptor

Niu Shin, Elizabeth Coates, Nicholas J. Murgolo, Kelley L. Morse, Marvin Bayne, Catherine D. Strader and Frederick J. Monsma
Molecular Pharmacology July 1, 2002, 62 (1) 38-47; DOI: https://doi.org/10.1124/mol.62.1.38
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