Monod-Wyman-Changeux Analysis of Ligand-Gated Ion Channel Mutants

  title={Monod-Wyman-Changeux Analysis of Ligand-Gated Ion Channel Mutants},
  author={Tal Einav and Rob Phillips},
We present a framework for computing the gating properties of ligand-gated ion channel mutants using the Monod-Wyman-Changeux (MWC) model of allostery. We derive simple analytic formulas for key functional properties such as the leakiness, dynamic range, half-maximal effective concentration ([EC50]), and effective Hill coefficient, and explore the full spectrum of phenotypes that are accessible through mutations. Specifically, we consider mutations in the channel pore of nicotinic acetylcholine… 
Evolutionary and functional insights into the mechanism underlying body-size-related adaptation of mammalian hemoglobin
It is suggested that Hb affinity and cooperativity reflect evolutionary and physiological adaptions that optimized tissue oxygen delivery that allows for both gross- and fine-tuning of tissue oxygen unloading to meet the distinct metabolic requirements of mammalian tissues for oxygen.
OBSOLETE: Ion Channels
  • C. Townsend
  • Materials Science
    Reference Module in Chemistry, Molecular Sciences and Chemical Engineering
  • 2021
The dual‐gate model for pentameric ligand‐gated ion channels activation and desensitization
Comparison with other classes of ligand‐ and voltage‐gated ion channels shows that this dual gate mechanism emerges as a common theme for the desensitization and inactivation properties of structurally unrelated ion channels.


Allostery and the Monod-Wyman-Changeux model after 50 years.
  • J. Changeux
  • Biology, Chemistry
    Annual review of biophysics
  • 2012
The Monod-Wyman-Changeux model is reexamined on the basis of a variety of regulatory proteins with known X-ray structures, raising new questions concerning the dynamics of the allosteric transitions and more complex supramolecular ensembles.
Thinking in cycles: MWC is a good model for acetylcholine receptor‐channels
The Monod, Wyman and Changeux formalism for allosteric proteins, originally developed for haemoglobin, is an excellent model for acetylcholine receptors and the gating equilibrium constants for receptors with zero, one or two bound agonist molecules, and the agonist association and dissociation rate constants from both the closed and open‐channel conformations are estimated experimentally.
Allosteric receptors after 30 years
Unliganded gating of acetylcholine receptor channels
Rate–equilibrium free-energy relationships for different regions of the protein show similar slopes (Φ values) for un- vs. diliganded gating, which suggests that the conformational pathway of the gating structural change is fundamentally the same with and without agonists.
The role of conserved leucines in the M2 domain of the acetylcholine receptor in channel gating.
The role of the conserved leucine is to set the mean open time of the channel through interactions with other regions of the receptor rather than to serve as the gate per se of the ion channel.
Relating ligand binding to activation gating in CNGA2 channels
The action of homotetrameric olfactory-type CNGA2 channels was studied in inside-out membrane patches by simultaneously determining channel activation and ligand binding, using the fluorescent cGMP analogue 8-DY547-cGMP as the ligand.
Emergence of ion channel modal gating from independent subunit kinetics
By mathematically modeling the basic biophysical events that control ion channel opening, a new principle for understanding the origin of modal gating is introduced, by modeling the kinetics of ligand binding and conformational change in the IP3R at the subunit level.
Channel gating governed symmetrically by conserved leucine residues in the M2 domain of nicotinic receptors
The results suggest that each of the five Leu 9′ residues participates independently and symmetrically in a key step in the structural transition between the closed and open states.
A kinetic mechanism for nicotinic acetylcholine receptors based on multiple allosteric transitions
A kinetic model is developed that links conformational interconversion rates to agonist binding and extends the general principles of the Monod-Wyman-Changeux model of allosteric transitions to the peripheral nicotinic acetylcholine receptor (nAChR), providing a physical basis for constructing more biologically realistic models of synaptic modulation that may be applied to artificial neural networks.