Analysis of histamine and modeling of ligand-receptor interactions in the histamine H(1) receptor for Magic Angle Spinning NMR studies.

Item does not contain fulltextOBJECTIVE AND DESIGN: Investigation of the principles of ligand-receptor interaction in histamine receptors can help to provide a solid foundation for structure-based drug design. Stable isotope labelling of the ligand 'Histamine' has been performed and 1D (13)C CP MAS and 2D Radio Frequency Dipolar Recoupling (RFDR) spectra for the ligand are presented. Hyperfine signals were well spread and did not suffer from any sizable line broadening. The production of H(1) receptor for Magic Angle Spinning NMR studies is currently in progress. TREATMENT: An agonist binding domain is proposed using homology modeling, database searches and mutagenesis data for the H(1) receptor. METHODS: Homology modeling, Database searches for Expressed sequence Tag (ESTs), Magic Angle Spinning Nuclear Magnetic Resonance analysis of the ligand histamine. RESULTS: The three-dimensional receptor model and mutagenesis studies suggest that the amine of the agonist histamine may form an ion pair with the TM III Asp, whereas the imidazole ring of histamine may associate with TM V Asp and Thr. CONCLUSIONS: Homology modeling studies confirms the absence of TM VIII in the H(1) receptor. According to the model the histamine in particular interacts with the transmembrane (TM) regions of the H(1) receptor structure, in particular TM helix III and V. This is in line with recent mutagenesis studies. Database search methods for ESTs have been used for electronic prediction of tissue distribution of H(1) receptor expression. The results indicate that the H(1) expression is highest in heart and skeletal muscle, which may be of importance for drug targeting

Solid-state NMR evidence for a protonation switch in the binding pocket of the H1 receptor upon binding of the agonist histamine

G protein coupled receptors (GPCRs) represent a major superfamily of transmembrane receptor proteins that are crucial in cellular signaling and are major pharmacological targets. While the activity of GPCRs can be modulated by agonist binding, the mechanisms that link agonist binding to G protein coupling are poorly understood. Here we present a method to accurately examine the activity of ligands in their bound state, even at low affinity, by solid-state NMR dipolar correlation spectroscopy and confront this method with the human

Stable isotope labelling of human histamine receptor H1R: prospects for structure-based drug design.

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