Protein Engineering, Vol. 14, No. 6, 409-414,
June 2001
© 2001 Oxford University Press
Differences in conformational properties of the second intracellular loop (IL2) in 5HT2C receptors modified by RNA editing can account for G protein coupling efficiency
Department of Physiology and Biophysics, Mount Sinai School of Medicine, One Gustave Levy Place, New York, NY 10029, USA
Adenosine-to-inosine RNA editing events that have been demonstrated for 5HT 2C receptors resulted in alterations of the amino acid sequence at positions 156, 158 and 160 in the intracellular loop 2 (IL2) region. The edited receptor isoforms were shown to have reduced basal activity, but similar maximum responses to agonist binding. To identify the molecular mechanism of these pharmacological effects of editing we explored the conformational properties of the edited IL2 in comparison with the wild type. The results from conformational studies of the IL2 isoforms, using biased Monte Carlo simulations with an implicit solvent model based on a screened Coulomb potential, show that the compared loops differ in their preferred spatial orientations as a result of differences in the conformational space that is accessible to them by energy criteria. For the IL2 of the unedited (5HT 2C-INI ) receptor, the preference for structures oriented towards the 7TM bundle is larger than for the 5HT 2C-VGV edited receptor. This difference in preferred orientation can affect the association of IL2 with other intracellular loop domains involved in G protein coupling and hence the coupling efficiency. The results illustrate the high sensitivity of the system to small changes in the interaction surface presented to other intracellular loops, and/or the G protein.
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