ISSN:
1573-4951
Keywords:
α-helical model system
;
Conformational analysis
;
Counterpoise method
;
Hartree-Fock calculations
;
Histamine H2 receptor
;
Molecular mechanics
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Summary Mutation studies on the histamine H2 receptor were reported by Gantz et al. [J. Biol. Chem., 267 (1992) 20840], which indicate that both the mutation of the fifth transmembrane Asp186 (to Ala186) alone or in combination with Thr190 (to Ala190) maintained, albeit partially, the cAMP response to histamine. Recently, we have shown that histamine binds to the histamine H2 receptor as a monocation in its proximal tautomeric form, and, moreover, we suggested that a proton is donated from the receptor towards the tele-position of the agonist, thereby triggering the biological effect [Nederkoorn et al., J. Mol. Graph., 12 (1994) 242; Eriks et al., Mol. Pharmacol., 44 (1993) 886]. These findings result in a close resemblance with the catalytic triad (consisting of Ser, His and Asp) found in serine proteases. Thr190 resembles a triad's serine residue closely, and could also act as a proton donor. However, the mutation of Thr190 to Ala190 — the latter is unable to function as a proton donor — does not completely abolish the agonistic cAMP response. At the fifth transmembrane α-helix of the histamine H2 receptor near the extracellular surface, another amino acid is present, i.e. Tyr182, so an alternative couple of amino acids, Tyr182 and Asp186, could constitute the histamine binding site at the fifth α-helix instead of the (mutated) couple Asp186 and Thr190. In the first part of our present study, this hypothesis is investigated with the aid of an oligopeptide with an α-helical backbone, which represents a part of the fifth transmembrane helix. Both molecular mechanics and ab initio data lead to the conclusion that the Tyr182/Asp186 couple is most likely to act as the binding site for the imidazole ring present in histamine.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00124476
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