Allosteric regulation
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
The site to which the effector binds is termed the allosteric site or regulatory site. Allosteric sites allow effectors to bind to the protein, often resulting in a conformational change and/or a change in protein dynamics.[1][2] Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are called allosteric inhibitors.
Allosteric regulations are a natural example of control loops, such as feedback from downstream products or feedforward from upstream substrates. Long-range allostery is especially important in cell signaling.[3] Allosteric regulation is also particularly important in the cell's ability to adjust enzyme activity.
The term allostery comes from the Ancient Greek allos (ἄλλος), "other", and stereos (στερεός), "solid (object)". This is in reference to the fact that the regulatory site of an allosteric protein is physically distinct from its active site. Allostery contrasts with substrate presentation which requires no conformational change for an enzyme's activation.
Models
Many allosteric effects can be explained by the concerted
Concerted model
The concerted model of allostery, also referred to as the symmetry model or
Sequential model
The sequential model of allosteric regulation holds that subunits are not connected in such a way that a conformational change in one induces a similar change in the others. Thus, all enzyme subunits do not necessitate the same conformation. Moreover, the sequential model dictates that molecules of a substrate bind via an
- subunits need not exist in the same conformation
- molecules of substrate bind via induced-fit protocol
- conformational changes are not propagated to all subunits
Morpheein model
The morpheein model of allosteric regulation is a dissociative concerted model.[8]
A morpheein is a homo-oligomeric structure that can exist as an ensemble of physiologically significant and functionally different alternate quaternary assemblies. Transitions between alternate morpheein assemblies involve oligomer dissociation, conformational change in the dissociated state, and reassembly to a different oligomer. The required oligomer disassembly step differentiates the morpheein model for allosteric regulation from the classic MWC and KNF models.
Ensemble models
Ensemble models of allosteric regulation enumerate an allosteric system's
Allosteric modulation
Energy sensing model
An example of this model is seen with the Mycobacterium tuberculosis, a bacterium that is perfectly suited to adapt to living in the macrophages of humans. The enzyme's sites serve as a communication between different substrates. Specifically between AMP and G6P. Sites like these also serve as a sensing mechanism for the enzyme's performance.[13]
Positive modulation
Positive allosteric modulation (also known as allosteric activation) occurs when the binding of one
Negative modulation
Negative allosteric modulation (also known as allosteric inhibition) occurs when the binding of one
Another example is
Another instance in which negative allosteric modulation can be seen is between
Types
Homotropic
A homotropic allosteric modulator is a
Heterotropic
A heterotropic allosteric modulator is a regulatory molecule that is not the enzyme's substrate. It may be either an activator or an inhibitor of the enzyme. For example, H+, CO2, and
As has been amply highlighted above, some allosteric proteins can be regulated by both their substrates and other molecules. Such proteins are capable of both homotropic and heterotropic interactions.[14]
Essential activators
Some allosteric activators are referred to as "essential", or "obligate" activators, in the sense that in their absence, the activity of their target enzyme activity is very low or negligible, as is the case with N-acetylglutamate's activity on carbamoyl phosphate synthetase I, for example.[16][17]
Non-regulatory allostery
A non-regulatory allosteric site is any non-regulatory component of an enzyme (or any protein), that is not itself an amino acid. For instance, many enzymes require sodium binding to ensure proper function. However, the sodium does not necessarily act as a regulatory subunit; the sodium is always present and there are no known biological processes to add/remove sodium to regulate enzyme activity. Non-regulatory allostery could comprise any other ions besides sodium (calcium, magnesium, zinc), as well as other chemicals and possibly vitamins.
Pharmacology
Allosteric modulation of a receptor results from the binding of allosteric modulators at a different site (a "
For example, the
More recent examples of drugs that allosterically modulate their targets include the calcium-mimicking cinacalcet and the HIV treatment maraviroc.
Allosteric sites as drug targets
Allosteric proteins are involved in, and are central in many diseases,[18][19] and allosteric sites may represent a novel drug target. There are a number of advantages in using allosteric modulators as preferred therapeutic agents over classic orthosteric ligands. For example, G protein-coupled receptor (GPCR) allosteric binding sites have not faced the same evolutionary pressure as orthosteric sites to accommodate an endogenous ligand, so are more diverse.[20] Therefore, greater GPCR selectivity may be obtained by targeting allosteric sites.[20] This is particularly useful for GPCRs where selective orthosteric therapy has been difficult because of sequence conservation of the orthosteric site across receptor subtypes.[21] Also, these modulators have a decreased potential for toxic effects, since modulators with limited co-operativity will have a ceiling level to their effect, irrespective of the administered dose.[20] Another type of pharmacological selectivity that is unique to allosteric modulators is based on co-operativity. An allosteric modulator may display neutral co-operativity with an orthosteric ligand at all subtypes of a given receptor except the subtype of interest, which is termed "absolute subtype selectivity".[21] If an allosteric modulator does not possess appreciable efficacy, it can provide another powerful therapeutic advantage over orthosteric ligands, namely the ability to selectively tune up or down tissue responses only when the endogenous agonist is present.[21] Oligomer-specific small molecule binding sites are drug targets for medically relevant morpheeins.[22]
Synthetic allosteric systems
There are many synthetic compounds containing several
In many multivalent
Online resources
Allosteric Database
Allostery is a direct and efficient means for regulation of biological macromolecule function, produced by the binding of a ligand at an allosteric site topographically distinct from the orthosteric site. Due to the often high receptor selectivity and lower target-based toxicity, allosteric regulation is also expected to play an increasing role in drug discovery and bioengineering. The AlloSteric Database (ASD)[30] provides a central resource for the display, search and analysis of the structure, function and related annotation for allosteric molecules. Currently, ASD contains allosteric proteins from more than 100 species and modulators in three categories (activators, inhibitors, and regulators). Each protein is annotated with detailed description of allostery, biological process and related diseases, and each modulator with binding affinity, physicochemical properties and therapeutic area. Integrating the information of allosteric proteins in ASD should allow the prediction of allostery for unknown proteins, to be followed with experimental validation. In addition, modulators curated in ASD can be used to investigate potential allosteric targets for a query compound, and can help chemists to implement structure modifications for novel allosteric drug design.
Allosteric residues and their prediction
Not all protein residues play equally important roles in allosteric regulation. The identification of residues that are essential to allostery (so-called “allosteric residues”) has been the focus of many studies, especially within the last decade.[31][32][33][34][35][36][37][38] In part, this growing interest is a result of their general importance in protein science, but also because allosteric residues may be exploited in biomedical contexts. Pharmacologically important proteins with difficult-to-target sites may yield to approaches in which one alternatively targets easier-to-reach residues that are capable of allosterically regulating the primary site of interest.[39] These residues can broadly be classified as surface- and interior-allosteric amino acids. Allosteric sites at the surface generally play regulatory roles that are fundamentally distinct from those within the interior; surface residues may serve as receptors or effector sites in allosteric signal transmission, whereas those within the interior may act to transmit such signals.[40][41]
See also
- ASD database
- Anharmonicity
- Competitive inhibition
- Cooperative binding
- Enzyme kinetics
- Protein dynamics
- Receptor theory
References
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External links
- Instant insight introducing a classification system for protein allostery mechanisms from the Royal Society of Chemistry