Relationships between Structural Dynamics and Functional Kinetics in Oligomeric Membrane Receptors |
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Authors: | Stuart J Edelstein Jean-Pierre Changeux |
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Institution: | † European Molecular Biology Laboratory-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom ‡ Centre National de la Recherche Scientifique, Institut Pasteur, Paris, France |
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Abstract: | Recent efforts to broaden understanding of the molecular mechanisms of membrane
receptors in signal transduction make use of rate-equilibrium free-energy
relationships (REFERs), previously applied to chemical reactions, enzyme
kinetics, and protein folding. For oligomeric membrane receptors, we distinguish
between a), the Leffler parameter αL, to
characterize the global transition state for the interconversion between
conformations; and b), the Fersht parameter,
?F, to assign the degree of progression
of individual residue positions at the transition state. For both
αL and
?F, insights are achieved by using
harmonic energy profiles to reflect the dynamic nature of proteins, as
illustrated with single-channel results reported for normal and mutant nicotinic
receptors. We also describe new applications of
αL based on published results. For
large-conductance calcium-activated potassium channels, data are satisfactorily
fit with an αL value of 0.65, in accord with
REFERs. In contrast, results reported for the flip conformational state of
glycine and nicotinic receptors are in disaccord with REFERs, since they yield
αL values outside the usual
limits of 0–1. Concerning published
?F values underlying the conformational
wave hypothesis for nicotinic receptors, we note that interpretations may be
complicated by variations in the width of harmonic energy profiles. |
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