Gating of Acetylcholine Receptor Channels: Brownian Motion across a Broad Transition State

Acetylcholine receptor channels (AChRs) are proteins that switch between stable "closed" and "open" conformations. In patch clamp recordings, diliganded AChR gating appears to be a simple, two-state reaction. However, mutagenesis studies indicate that during gating dozens of resi...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 5; pp. 1408 - 1412
Main Authors Auerbach, Anthony, Fersht, Alan R.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 01.02.2005
National Acad Sciences
Subjects
Agonists
Biological Sciences
Biophysics
Brownian motion
Cholinergic Agonists - pharmacology
Cholinergic receptors
Computer Simulation
Dead time
Energy
Ion Channel Gating - physiology
Ion Channels - chemistry
Ion Channels - drug effects
Ion Channels - physiology
Isomerization
Kinetics
Mathematical constants
Models, Biological
Models, Theoretical
Musical intervals
Protein Conformation
Proteins
Receptors, Cholinergic - chemistry
Receptors, Cholinergic - drug effects
Receptors, Cholinergic - physiology
Transmitters
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Summary:Acetylcholine receptor channels (AChRs) are proteins that switch between stable "closed" and "open" conformations. In patch clamp recordings, diliganded AChR gating appears to be a simple, two-state reaction. However, mutagenesis studies indicate that during gating dozens of residues across the protein move asynchronously and are organized into rigid body gating domains ("blocks"). Moreover, there is an upper limit to the apparent channel opening rate constant. These observations suggest that the gating reaction has a broad, corrugated transition state region, with the maximum opening rate reflecting, in part, the mean first-passage time across this ensemble. Simulations reveal that a flat, isotropic energy profile for the transition state can account for many of the essential features of AChR gating. With this mechanism, concerted, local structural transitions that occur on the broad transition state ensemble give rise to fractional measures of reaction progress (Φ values) determined by rate-equilibrium free energy relationship analysis. The results suggest that the coarse-grained AChR gating conformational change propagates through the protein with dynamics that are governed by the Brownian motion of individual gating blocks.
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Abbreviations: O, open; C, closed; ACh, acetylcholine; AChR, ACh receptor channel; CL, low-affinity C; CH, high-affinity C; REFER, rate-equilibrium free-energy relationship.
This paper was submitted directly (Track II) to the PNAS office.
E-mail: auerbach@buffalo.edu.
Edited by Alan R. Fersht, University of Cambridge, Cambridge, United Kingdom
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0406787102