Related Experiment Video
Updated: Jun 12, 2026
09:42
Unraveling Entropic Rate Acceleration Induced by Solvent Dynamics in Membrane Enzymes
Published on: January 16, 2016
Relationships between structural dynamics and functional kinetics in oligomeric membrane receptors
Stuart J Edelstein1, Jean-Pierre Changeux
1European Molecular Biology Laboratory-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK. stuart.edelstein@unige.ch
Biophysical Journal
|May 21, 2010
Summary
Rate-equilibrium free-energy relationships (REFERs) offer insights into membrane receptor dynamics. New applications of the Leffler parameter (alpha(L)) reveal conformational changes in ion channels, though some receptor states challenge existing models.
Area of Science:
- Biochemistry and Biophysics
- Molecular Biology
- Structural Biology
Background:
- Membrane receptors are crucial for signal transduction.
- Rate-equilibrium free-energy relationships (REFERs) are increasingly used to study protein dynamics.
- Understanding conformational changes in receptors is key to deciphering their function.
Purpose of the Study:
- To apply and extend the use of REFERs, specifically the Leffler parameter (alpha(L)) and Fersht parameter (varphi(F)), to analyze the molecular mechanisms of oligomeric membrane receptors.
- To investigate the conformational dynamics of nicotinic acetylcholine receptors and other ion channels using harmonic energy profiles.
- To evaluate the applicability of REFERs to different receptor systems and conformational states.
Main Methods:
- Application of the Leffler parameter (alpha(L)) to characterize global transition states in receptor conformational interconversion.
- Utilizing the Fersht parameter (varphi(F)) to assess the progression of individual residues at the transition state.
- Analysis of single-channel recordings and published data using harmonic energy profiles to model protein dynamics.
Main Results:
- The Leffler parameter (alpha(L)) successfully characterized conformational transitions in large-conductance calcium-activated potassium channels, yielding a value of 0.65 consistent with REFERs.
- Analysis of the flip conformational state in glycine and nicotinic receptors yielded alpha(L) values outside the typical 0-1 range, indicating a potential discrepancy with REFER predictions.
- Published varphi(F) values for nicotinic receptors suggest that variations in harmonic energy profile width may complicate interpretations of the conformational wave hypothesis.
Conclusions:
- REFERs, particularly alpha(L), provide a valuable framework for understanding the transition states of membrane receptor conformational changes.
- Certain receptor conformational states, like the flip state in glycine and nicotinic receptors, may require refined models or extensions of REFERs.
- Further investigation into the factors influencing harmonic energy profiles is necessary for accurate interpretation of parameters like varphi(F) in complex receptor systems.
Related Concept Videos
01:58Cooperative Allosteric Transitions
Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
01:58Cooperative Allosteric Transitions
Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
01:29The Two-State Receptor Model
The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with one...
The binding affinity of a drug determines its interaction with one...
01:30Assembly of Signaling Complexes
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
01:09Multi-pass Transmembrane Proteins and β-barrels
In multi-pass transmembrane proteins, the polypeptide chain crosses the membrane more than once. The transmembrane polypeptide chain either forms an α-helix or β-strand structure. α-Helix containing multi-pass transmembrane proteins are ubiquitous, whereas β-strand containing ones are mainly found in gram-negative bacteria, mitochondria, and chloroplasts.
α-Helix containing multi-pass transmembrane proteins
Multi-pass transmembrane proteins such as G-protein-linked receptors (GPCRs) and...
α-Helix containing multi-pass transmembrane proteins
Multi-pass transmembrane proteins such as G-protein-linked receptors (GPCRs) and...
01:24Protein Diffusion in the Membrane
Proteins show rotational as well as lateral diffusion across the membrane. The lateral diffusion of proteins was confirmed through the cell fusion experiment where mouse and human cells were fused, resulting in hybrid cells. When the human and mouse cells fused, the specific membrane proteins on human and mouse cells were marked with the red and green-fluorescent markers, respectively. Initially, the red and green fluorescence was located on the respective hemisphere of the cell. As time...