The agonistic binding site at the histamine H2 receptor. I. Theoretical investigations of histamine binding to an oligopeptide mimicking a part of the fifth transmembrane alpha-helix

Journal of Computer-aided Molecular Design
P H NederkoornH Timmerman

Abstract

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 alpha-helix of the histamine H2 receptor near the extracellular surface, another amino acid is present, i.e. Tyr182, which could act as a proton donor. Furthermore, Tyr18...Continue Reading

References

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Citations

Jun 19, 1998·Current Opinion in Structural Biology·R A Friesner, M D Beachy
Aug 12, 1999·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·M J SmitR Leurs
Dec 21, 2012·Trends in Pharmacological Sciences·Roland SeifertArmin Buschauer
Jun 11, 2004·Chirality·Ran Kafri, Doron Lancet
Jul 28, 1999·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·M SchuilingH Meurs
Jan 8, 2011·Journal of Molecular Graphics & Modelling·Xianqiang SunYun Tang

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