Allostery – Definition, Mechanism & Significance
Allostery describes the regulation of proteins through binding of a molecule to a site outside the active center. A central principle of biochemistry.
Things worth knowing about "Allostery"
Allostery describes the regulation of proteins through binding of a molecule to a site outside the active center. A central principle of biochemistry.
What is Allostery?
Allostery (from Greek “allos” = other and “stereos” = solid, space) is a fundamental regulatory mechanism in biochemistry. It occurs when the binding of a molecule – known as the allosteric effector or ligand – to an allosteric site (a site distinct from the active center) changes the three-dimensional structure (conformation) of a protein and thereby alters its biological activity.
Allostery is essential for the fine-tuned regulation of biological processes and is found in enzymes, receptors, transport proteins, and transcription factors.
Mechanism of Action
When an effector binds to the allosteric site, it induces a conformational change throughout the protein. This structural change can either increase or decrease the protein activity:
- Allosteric activation: Binding of the effector increases protein activity, for example by making the active site more accessible.
- Allosteric inhibition: Binding of the effector decreases protein activity, for example by distorting or blocking the active site.
A classic example of allosteric inhibition is feedback inhibition: the end product of a metabolic pathway allosterically inhibits the first enzyme of that pathway, preventing overproduction.
Cooperativity as a Special Form of Allostery
Many allosteric proteins consist of multiple subunits (they are oligomeric). The binding of a ligand to one subunit can alter the affinity of other subunits for the same or a different ligand. This phenomenon is called cooperativity.
- Positive cooperativity: Binding of one ligand facilitates binding of additional ligands (example: oxygen binding to hemoglobin).
- Negative cooperativity: Binding of one ligand reduces the affinity for additional ligands.
The most well-known example is hemoglobin: the binding of the first oxygen molecule facilitates the binding of further oxygen molecules to the other subunits – a vital mechanism for oxygen transport in the blood.
Models of Allostery
Several models have been developed to explain allosteric phenomena:
- MWC Model (Monod-Wyman-Changeux Model): All subunits of a protein switch simultaneously between two conformational states (T-state = tense, R-state = relaxed).
- KNF Model (Koshland-Nemethy-Filmer Model): Conformational changes occur stepwise, triggered by the sequential binding of ligands.
- Extended allosteric model: More recent research shows that allosteric transitions can also occur spontaneously without ligand binding (dynamic allostery).
Clinical and Pharmacological Significance
Allostery plays a prominent role in modern medicine and pharmacology. Allosteric modulators are substances that selectively bind to allosteric sites and thereby influence the activity of target proteins:
- Positive allosteric modulators (PAMs) enhance the activity of a protein without directly activating it.
- Negative allosteric modulators (NAMs) reduce the activity of a protein.
Examples of drugs that act allosterically:
- Benzodiazepines (e.g. diazepam): positive allosteric modulators of the GABAA receptor, enhancing the inhibitory effect of GABA.
- Metformin: allosterically activates the enzyme AMP-activated protein kinase (AMPK).
- Inhibitors of aspartate transcarbamoylase (ATCase): a classical model system for allosteric regulation in biochemistry.
Because allosteric sites are often structurally more unique than active sites, they offer targets for more selective drugs with fewer side effects.
Allostery in Diagnostics and Research
In biomedical research, allostery is intensively studied to develop new therapeutic strategies for diseases such as cancer, metabolic disorders, neurological conditions, and infectious diseases. Modern techniques such as cryo-electron microscopy and computational simulations help to understand allosteric mechanisms at the molecular level.
References
- Monod J, Wyman J, Changeux JP. On the nature of allosteric transitions: A plausible model. Journal of Molecular Biology. 1965;12(1):88-118.
- Nussinov R, Tsai CJ. Allostery in disease and in drug discovery. Cell. 2013;153(2):293-305.
- Berg JM, Tymoczko JL, Stryer L. Biochemistry. 9th edition. W.H. Freeman and Company, 2019.
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