Molecular basis for the interaction of histamine with the histamine H2 receptor.

Gantz, Ira; DelValle, John; Wang, Lidong; Tashiro, Takao; Munzert, Gerd; Guo, Yingqi; Konda, Yoshitaka; Yamada, Tadataka

doi:10.1016/s0021-9258(19)36764-x

Cited by 126 publications

(27 citation statements)

References 11 publications

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“…Figure S32). The probability for an interaction with these residues is supported by the fact that they were proven to act as key player in aminergic GPCR activation and ligand binding, − or to account for receptor selectivity (D186 5.42 at h H 2 R) . Interestingly, both 5 and 58 showed high binding affinities at h H 2 R ( K i < 100 nM), low affinities at the h H 1 R ( K i > 1 μM), but varying affinities at the h H 3 R and h H 4 R ( 5 : K i < 100 nM; 58 : K i > 1 μM).…”

Section: Resultsmentioning

confidence: 99%

“…The probability for an interaction with these residues is supported by the fact that they were proven to act as key player in aminergic GPCR activation and ligand binding, 27−30 or to account for receptor selectivity (D186 5.42 at hH 2 R). 31 Interestingly, both 5 and 58 showed high binding affinities at hH 2 R (K i < 100 nM), low affinities at the hH 1 R (K i > 1 μM), but varying affinities at the hH 3 R and hH 4 R (5: K i < 100 nM; 58: K i > 1 μM). Although, by contrast, the monomeric imidazole-type analogue 129 bound unexpectedly poor to the hH 2 R, and, comparable to the dimeric compounds, also to the hH 1 R (K i > 1 μM), it bound to the hH 3 R and hH 4 R with high affinity (K i < 100 nM).…”

Section: Introductionmentioning

confidence: 93%

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Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H₂ Receptor Agonists

et al. 2018

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On the basis of the long-known prototypic pharmacophore 3-(1H-imidazol-4-yl)propylguanidine (SK&F 91486, 2), monomeric, homodimeric, and heterodimeric bisalkylguanidine-type histamine H2 receptor (H2R) agonists with various alkyl spacers were synthesized. Aiming at increased H2R selectivity of the ligands, the imidazol-4-yl moiety was replaced by imidazol-1-yl, 2-aminothiazol-5-yl or 2-amino-4-methylthiazol-5-yl according to a bioisosteric approach. All compounds turned out to be partial or full agonists at the h/gp/rH2R. The most potent analogue, the thiazole-type heterodimeric ligand 63 (UR-Po461), was a partial agonist (Emax = 88%) and 250 times more potent than histamine (pEC50: 8.56 vs 6.16, gpH2R, atrium). The homodimeric structures 56 (UR-Po395) and 58 (UR-Po448) exhibited the highest hH2R affinities (pKi: 7.47, 7.33) in binding studies. Dimeric amino(methyl)thiazole derivatives, such as 58, generated an increased hH2R selectivity compared to the monomeric analogues, e.g., 139 (UR-Po444). Although monomeric ligands showed up lower affinities and potencies at the H2R, compounds with a short alkylic side chain like 129 (UR-Po194) proved to be highly affine hH4R ligands.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H₂ Receptor Agonists

et al. 2018

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“…In accordance with the helical periodicity, position 5.46 has been proven essential for most agonist binding [Strader et al, 1989a;Wang et al, 1991;Kao et al, 1992;Mansour et al, 1992;Pollock et al, 1992;Leurs et al, 1994;Ohta et al, 1994;Moguilevsky et al, 1995], and less frequently for antagonist binding [Gantz et al, 1992;Kao et al, 1992;Leurs et al, 1994]. This position is predominantly occupied by small amino acid residues (21% G, 20% S, and 19% A), but larger residues occur in several GPCRs (e.g., H in rhodopsin, Y in endothelin, and W in adenosine A 1 and A 3 receptors).…”

Section: Transmembrane Domain 5 (Tm5)mentioning

confidence: 94%

Molecular architecture of G protein-coupled receptors

1996

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This review of the current literature on mutations in G protein-coupled receptors (GPCRs) of the rhodopsin-related family intends to draw inferences from amino acid sequences for single receptors and multiple sequence alignments with regard to the molecular architecture of this class of receptors. For this purpose a comprehensive list of mutations within the transmembrane helical regions (TMs; over 390 mutations from 38 different receptor subtypes) and their effects on function was compiled, and an alignment of known GPCR sequences (over 150 separate sequences) was made. Regions most prominently involved in ligand binding are located in TMs 3, 5, 6, and 7. Position 3.32 in TM3 is occupied by a D in all biogenic amine receptors (sequence conservation) but may be occupied by uncharged residues in other receptors while its role in ligand binding is analogous (function conservation). TMs 5, 6, and 7 display considerable sequence conservation throughout the majority of GPCRs investigated, but not necessarily at those positions involved in ligand binding. However, considerable function conservation is observed for positions 5.42 (frequently hydrophilic), 5.46 (small amino acids required for agonist binding to "small ligand" receptors), 6.52 and 7.39 (high variability), and 7.43 (frequently aromatic). A general conclusion of this review is that there is overwhelming conservation of structure-function correlates among GPCRs. Thus, it is now possible to cross-correlate the results of mutagenesis studies between GPCRs of different subfamilies, and to use those results to predict the function of specific residues in new GPCR sequences.

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“…Histamine receptor mutation data. ,− ,− ,− Data is shown for the consensus binding pocket defined using structure-based generic position numbers from GPCRdb . Wild-type residues for the orthologues involved in mutation studies, and the mutant residue are shown (note that only the mutations which have a data point shown in the table were actually carried out, the table is organized for comparability among orthologues).…”

Section: Histamine Receptor Mutationsmentioning

confidence: 99%

Aminergic GPCR–Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data

Vass¹,

Podlewska

Esch³

et al. 2018

J. Med. Chem.

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The aminergic family of G protein-coupled receptors (GPCRs) plays an important role in various diseases and represents a major drug discovery target class. Structure determination of all major aminergic subfamilies has enabled structurebased ligand design for these receptors. Site-directed mutagenesis data provides an invaluable complementary source of information for elucidating the structural determinants of binding of different ligand chemotypes. The current study provides a comparative analysis of 6692 mutation data points on 34 aminergic GPCR subtypes, covering the chemical space of 540 unique ligands from mutagenesis experiments and information from experimentally determined structures of 52 distinct aminergic receptor−ligand complexes. The integrated analysis enables detailed investigation of structural receptor−ligand interactions and assessment of the transferability of combined binding mode and mutation data across ligand chemotypes and receptor subtypes. An overview is provided of the possibilities and limitations of using mutation data to guide the design of novel aminergic receptor ligands.

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Molecular basis for the interaction of histamine with the histamine H2 receptor.

Cited by 126 publications

References 11 publications

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H₂ Receptor Agonists

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H₂ Receptor Agonists

Molecular architecture of G protein-coupled receptors

Aminergic GPCR–Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data

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Molecular basis for the interaction of histamine with the histamine H2 receptor.

Cited by 126 publications

References 11 publications

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H2 Receptor Agonists

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H2 Receptor Agonists

Molecular architecture of G protein-coupled receptors

Aminergic GPCR–Ligand Interactions: A Chemical and Structural Map of Receptor Mutation Data

Contact Info

Product

Resources

About

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H₂ Receptor Agonists

Highly Potent, Stable, and Selective Dimeric Hetarylpropylguanidine-Type Histamine H₂ Receptor Agonists