Modelling and mutation studies on the histamine H1-receptor agonist binding site reveal different binding modes for H1-agonists: Asp116 (TM3) has a constitutive role in receptor stimulation

Laak, Antonius ter; Timmerman, H.; Leurs, Rob; Nederkoorn, Paul H. J.; Smit, Martine J.; Kelder, Gabriëlle M. Donné-Op den

doi:10.1007/bf00125173

Cited by 51 publications

(33 citation statements)

References 21 publications

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“…Modeling and mutational studies ter Laak et al, 1995) suggest that the lysine 200 in the H1 receptor is important for receptor activation. Mutation of corresponding H3 residue leucine 199 reduced the potency and efficacy of agonists in the cAMP assay.…”

Section: Discussionmentioning

confidence: 99%

The Role of Transmembrane Helix 5 in Agonist Binding to the Human H3 Receptor

Uveges¹,

Kowal²,

Zhang³

et al. 2002

J Pharmacol Exp Ther

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We have used alanine scanning mutagenesis to identify residues in transmembrane domain 5 of the histamine H3 receptor that are important for agonist binding. All of the mutants generated were functionally expressed as demonstrated by their ability to bind [125 I]iodoproxyfan with comparable affinity to the wild-type receptor and their ability to inhibit forskolin-stimulated cAMP formation when activated by histamine. Many mutations produced small changes in the potency of histamine, but the most pronounced reduction in potency and affinity of the agonists, histamine, R-␣-methylhistamine, imetit, and impentamine, was seen with mutation of glutamate 206. Our modeling suggests that this residue plays a key role in ligand binding by interacting with the imidazole ring of histamine. Interestingly, L199A greatly reduced agonist potency in functional assays but had only minor effects on agonist affinity, implicating a role for this residue in the mechanism of receptor activation. We also studied the functional effects of the mutations by linking the receptor to calcium signaling using a chimeric G protein. A comparison of the two functional assays demonstrated contrasting effects on agonist activity. Histamine, imetit, and impentamine were full agonists in the cAMP assay, but imetit exhibited only partial agonist activity through the chimeric G protein. Furthermore, impentamine, another potent agonist in the cAMP assay, was only able to activate the E206A mutant in the calcium assay despite being inactive at the wild-type receptor. These observations suggest that the agonist receptor complexes formed by these three different H3 agonists are not conformationally equivalent.

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Section: Discussionmentioning

confidence: 99%

The Role of Transmembrane Helix 5 in Agonist Binding to the Human H3 Receptor

Uveges¹,

Kowal²,

Zhang³

et al. 2002

J Pharmacol Exp Ther

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“…Timmermann and Leurs published the first atomistic models of the histamine H1 receptor (H1R) in 1995 [7] and 1999 [8]. In these first modeling attempts, the authors proposed binding modes for agonists [7] and antagonists [8] using a homology model of the guinea pig H1R based on the low-resolution bacteriorhodopsin structure.…”

Section: H1 Receptormentioning

confidence: 99%

“…In these first modeling attempts, the authors proposed binding modes for agonists [7] and antagonists [8] using a homology model of the guinea pig H1R based on the low-resolution bacteriorhodopsin structure. Despite the fact that bacteriorhodopsin is not a GPCR and it lacks some of the conserved GPCR sequence motifs the models provided useful insights.…”

Section: H1 Receptormentioning

confidence: 99%

“…Although bacteriorhodopsin is a light-driven proton pump this structure has been used to develop early homology models for GPCRs. Timmermann and Leurs published the first atomistic model of the histamine H1 receptor in 1995 [7] investigating the binding modes of histamine, 2-methylhistamine and 2-phenyl-histamine as agonists and cyproheptadine as antagonist on bacteriorhodopsin-based homology models. This model has been further refined in a subsequent study analyzing the relationship of the H1 antagonist pharmacophore model and the binding mode of H1 antagonists in a guinea pig H1R homology model [8].…”

Section: Introductionmentioning

confidence: 99%

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Structure-based discovery and binding site analysis of histamine receptor ligands

Kingsford-Adaboh

Keserü

2016

Expert Opinion on Drug Discovery

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Introduction: Application of structure-based drug discovery in histamine receptor projects was previously hampered by the lack of experimental structures. The publication of the first X-ray structure of the histamine H1 receptor has been followed by several successful virtual screens and binding site analysis studies of H1-antihistamines. This structure together with several other recently solved aminergic G-protein coupled receptors (GPCRs) enabled the development of more realistic homology models for H2, H3 and H4 receptors. Areas covered: In this paper, we review the development of histamine receptors models and their application on drug discovery. Expert opinion: In our opinion, the application of atomistic histamine receptor models played a significant role in understanding key ligand-receptor interactions as well as in the discovery of novel chemical starting points. The recently solved H1 receptor structure is a major milestone in structure-based drug discovery, however our analysis also demonstrate that for building H3 and H4 receptor homology models other GPCRs may be more suitable as a template. For these receptors we envisage that the development of higher quality homology models will significantly contribute to the discovery and optimization of novel H3 and H4 ligands.

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“…14 -16). Previously, we also developed a three-dimensional computer model of the histamine H 1 receptor based on the homology with BR, incorporating the results obtained from mutagenesis studies on the agonist binding site (17). In the present study this computer model of the H 1 receptor was combined with a pharmacophoric model of the H 1 antagonistic binding site (18).…”

mentioning

confidence: 99%

Mutational Analysis of the Antagonist-binding Site of the Histamine H1 Receptor

Wieland

Laak²,

Smit

et al. 1999

Journal of Biological Chemistry

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109

115

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Since the initial discovery of the role of histamine in allergic conditions (1) serious efforts have been made to develop drugs that inhibit the actions of histamine. Already in 1933, Fourneau and Bovet (2) reported the first "antihistamine" piperoxan. Following this finding many potent H 1 antagonists that can be considered as variations of diaryl-substituted ethylamines (e.g. diphenhydramine and mepyramine) have been developed (for review see Ref.3). These "first generation" H 1 antagonists are quite effective in humans in allergic rhinitis and urticaria, but because of central nervous system penetration and central H 1 receptor blockade their clinical use is hampered by sedative side effects (3-5). A "second generation" of nonsedative H 1 antagonists (e.g. astemizole, acrivastine, cetirizine, loratidine, and terfenadine) has recently been developed (for review see Ref.3). Their altered pharmacokinetics result in good clinical effectiveness combined with a strongly reduced sedative potential (3-5).The development of H 1 antagonists has so far been directed by traditional medicinal chemistry (3). With the availability of the genetic information of the histamine H 1 receptor (6), the rationalization of drug-protein interaction has become a major challenge for this therapeutically important class of drugs. Like all aminergic G-protein coupled receptors (GPCR), 1 the H 1 receptor contains an aspartate residue (Asp 116 ) in transmembrane domain (TM) III (6), that is involved in the binding of the protonated amine function found in both agonists and antagonists structures (7,8). Mutagenesis studies have furthermore shown that the imidazole ring of histamine is accommodated by Lys 200 and Asn 207 in TM V (9, 10). In view of the low sequence similarity between GPCRs and bacteriorhodopsin (BR) much controversy exists on the validity of models derived for GPCRs based on the homology with BR (11-13). Nevertheless, despite the speculative nature of BRderived GPCR models they have been quite helpful in understanding and predicting drug-receptor interactions for a variety of receptors (see e.g. Refs. 14 -16). Previously, we also developed a three-dimensional computer model of the histamine H 1 receptor based on the homology with BR, incorporating the results obtained from mutagenesis studies on the agonist binding site (17). In the present study this computer model of the H 1 receptor was combined with a pharmacophoric model of the H 1 antagonistic binding site (18). This ligand-based model for the H 1 antagonistic binding site is based upon an interaction of the protonated amine function of various first generation, semi-rigid H 1 antagonists with an aspartate residue (Asp 116 in the guinea pig H 1 receptor) (18) and precisely positions the cis-and trans-aromatic rings of the H 1 antagonists relative to the C ␣ and C ␤ carbon atoms of this aspartate residue. Combining the three-dimensional receptor model and the ligand-based pharmacophoric model of the H 1 antagonist binding site resulted in the prediction of interactions...

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Modelling and mutation studies on the histamine H1-receptor agonist binding site reveal different binding modes for H1-agonists: Asp116 (TM3) has a constitutive role in receptor stimulation

Cited by 51 publications

References 21 publications

The Role of Transmembrane Helix 5 in Agonist Binding to the Human H3 Receptor

The Role of Transmembrane Helix 5 in Agonist Binding to the Human H3 Receptor

Structure-based discovery and binding site analysis of histamine receptor ligands

Mutational Analysis of the Antagonist-binding Site of the Histamine H1 Receptor

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