Ligand-activated trans-membrane proton transfer in beta 1-adrenergic and m2-muscarinic receptors.
An alignment of beta 1-adrenoceptor alpha-helices on the bacteriorhodopsin model is compared with an equivalent alignment to m2-muscarinic alpha-helices. A proposed mechanism of ligand-activated trans-membrane proton transfer within alpha-helices III, IV, V, VI and VII of the beta 1-adrenoceptor involving activation of a Tyr377-Arg156-Tyr157 proton shuttle by two hydrogen bond proton donor interactions of the natural ligand, nor-adrenaline is found to have an equivalent representation in the m2-muscarinic receptor. Activation of Tyr377 in the beta 1-adrenoceptor is achieved by a direct hydrogen bond interaction of the para-hydroxy moiety and by an indirect action of the beta-hydroxyl group involving reversal of a hydrogen bond relay. Activation of Tyr440 in the m2-muscarinic receptor is achieved directly by Tyr403 and indirectly by reversal of the equivalent hydrogen bond relay Asn432-Ser433-Ser110-Asn436. The necessity for the beta-hydroxyl group in adrenoceptor ligands is attributed to the presence of Val142 and equivalent residues which function to isolate reversal of the hydrogen bond relay by the protonated amine moiety. A simple modification to the mechanism of the previously proposed hydrogen-bond relay brings all hydrogen bonds to within accepted tolerances (+/ 0.2 A) and the energetics of proton shuttle activation are theoretically evaluated.
Zeneca Pharmaceuticals, Macclesfield, Cheshire, England, UK.
D
D
Timms
A J
AJ
Wilkinson
D R
DR
Kelly
K J
KJ
Broadley
R H
RH
Davies
D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008322:Mammals; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011522:Protons; D051381:Rats; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry* / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D008024:Ligands; D011522:Protons; D018342:Receptors, Adrenergic, beta-1; D011976:Receptors, Muscarinic