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


METHODS
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.
Prasad Ratnala
V R
VR
Leiden Institute of Chemistry, Gorlaeus Laboratoria, Einsteinweg 55, 2300 Leiden, The Netherlands. r.prasad@fwncism1.leidenuniv.nl
Hulsbbergen
F B
FB
de Groot
H J M
HJ
de Grip
W J
WJ
D055592:Biophysical Phenomena; D001703:Biophysics; D019295:Computational Biology; D004591:Electrophoresis, Polyacrylamide Gel; D006632:Histamine / Q000737:chemistry*; D006801:Humans; D007257:Information Theory; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy; D011487:Protein Conformation; D011969:Receptors, Histamine H1 / Q000737:chemistry*; D014018:Tissue Distribution
D011969:Receptors, Histamine H1; D006632:Histamine