Cooperativity of allosteric receptors

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• The Hill coefficient (nH) is commonly used to quantify ligand binding cooperativity in allosteric receptors.
• However, interpreting nH values for conformational state transitions can be ambiguous due to reference state variability.
• A hyperbolic binding curve (nH=1) serves as the reference for cooperative ligand binding.

Purpose of the Study:

• To propose a refined method for quantifying cooperativity in allosteric receptor conformational transitions.
• To address the limitations of the standard Hill coefficient (nH) in specific contexts.
• To establish a more accurate measure of effective cooperativity.

Main Methods:

• Comparing Hill coefficients (nH) for cooperative ligand binding versus conformational state transitions.
• Defining effective cooperativity as the ratio of these nH values.
• Utilizing dose-response curves of homopentameric α7 nicotinic receptors (wild-type and mutant) as a model system.
• Discussing the impact of normalization on dose-response curves for allosteric monomers.

Main Results:

• For conformational transitions, curves with nH>1 are observed, while the equivalent allosteric monomer typically has nH<1.
• The ratio of these nH values accurately reflects effective cooperativity, equaling N (oligomer protomer number) for concerted transitions (Monod-Wyman-Changeux model).
• Normalization of dose-response curves in allosteric monomers can mask the allosteric range and artificially inflate apparent cooperativity.

Conclusions:

• A novel ratio of Hill coefficients provides a robust measure of effective cooperativity for allosteric receptor conformational changes.
• This approach clarifies the quantitative relationship between ligand concentration and receptor state transitions.
• The concepts of equivalent monomer and allosteric range, originally proposed by Crick and Wyman, are validated and highlighted.