Abstract
The mu opioid receptor (MOR) is a Class A G protein-coupled receptor. Naloxone, a MOR antagonist, has been shown experimentally to have partial agonist properties in a transmembrane helix 4 (TMH4) S196L/A MOR and full agonist activity in a triple mutant that combines the TMH4 mutation (S196L) with two mutations in TMH7, T327A and C330S (Claude-Geppert et. al, J. Pharmacol. Exp. Ther. 2005). We hypothesized that the loss of a serine in TMH4, the loss of a threonine in TMH7 and addition of a serine in TMH7 will modify the wild-type (WT) conformation of both helices and that this change may result in naloxone preferring the MOR activated state. The hydrogen bonding capacity of Ser/Thr residues in α-helices can be satisfied by an intrahelical hydrogen bond interaction, in either the g- or g+ conformation, between the O-γ atom and the i-3 or i-4 carbonyl oxygen . Ser/Thr residues in the g- conformation can induce a bend in an α-helix (Ballesteros et. al, Biophysical J. 2000), as well as changes in wobble angle and face shift (Zhang et al. Mol. Pharmacol. 2005). Using the Monte Carlo/simulated annealing technique, Conformational Memories, we explored the effect of Ser/Thr in g- on the conformation of WT MOR and the mutant TMH4 and TMH7s (Whitnell et. al, J. Comput. Chem. 2007). For TMH4, the (wobble angle, face shift) was found to be (-36.4°, 22.1°) for WT vs. (5.7°, 4.6°) for S196L , causing the top of TMH4 to move away from the TMH bundle. For TMH7, a significant difference was found in the average wobble angles of WT(52.52° ± 21.72°) vs. mutant TMH7 (120.55° ± 23.43°), causing the top of TMH7 to move into the bundle. [Support: NIH DA023905 and DA021358]
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