Allosteric regulation
Encyclopedia
In biochemistry
, allosteric regulation is the regulation of an enzyme
or other protein
by binding an effector
molecule at the protein's allosteric site (that is, a site other than the protein's active site
). 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. The term allostery comes from the Greek
allos (ἄλλος), "other", and stereos (στερεὀς), "solid (object)", in reference to the fact that the regulatory site of an allosteric protein is physically distinct from its active site. 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
.
put forth by Monod
, Wyman, and Changeux
, or by the sequential model
described by Koshland, Nemethy, and Filmer. Both postulate that enzyme subunit
s exist in one of two conformations
, tensed (T) or relaxed (R), and that relaxed subunits bind substrate more readily than those in the tense state. The two models differ most in their assumptions about subunit interaction and the preexistence of both states.
, postulates that enzyme subunits are connected in such a way that a conformational change in one subunit is necessarily conferred to all other subunits. Thus, all subunits must exist in the same conformation. The model further holds that, in the absence of any ligand (substrate or otherwise), the equilibrium favours one of the conformational states, T or R. The equilibrium can be shifted to the R or T state through the binding of one ligand
(the allosteric effector or ligand) to a site that is different from the active site (the allosteric site).
, the active site, in essence, forms a glove around its substrate. While such an induced fit converts a subunit from the tensed state to relaxed state, it does not propagate the conformational change to adjacent subunits. Instead, substrate-binding at one subunit only slightly alters the structure of other subunits so that their binding sites are more receptive to substrate. To summarize:
enhances the attraction between substrate molecules and other binding sites. An example is the binding of oxygen
molecules to hemoglobin
, where oxygen is effectively both the substrate
and the effector. The allosteric, or "other", site is the active site of an adjoining protein subunit
. The binding of oxygen to one subunit induces a conformational change in that subunit that interacts with the remaining active sites to enhance their oxygen affinity.
decreases the affinity for substrate at other active sites. For example, when 2,3-BPG
binds to an allosteric site on hemoglobin, the affinity for oxygen of all subunits decreases. This is when a regulator is absent from the binding site.
Another example is strychnine
, a convulsant
poison, which acts as an allosteric inhibitor of the glycine receptor
. Glycine
is a major post-synaptic
inhibitory neurotransmitter
in mammal
ian spinal cord
and brain stem
. Strychnine acts at a separate binding site on the glycine receptor in an allosteric manner; i.e., its binding lowers the affinity of the glycine receptor for glycine. Thus, strychnine inhibits the action of an inhibitory transmitter, leading to convulsions.
for its target enzyme
, as well as a regulatory molecule of the enzyme's activity. It is typically an activator of the enzyme.
Some allosteric proteins can be regulated by both their substrates and other molecules. Such proteins are capable of both homotropic and heterotropic interactions.
") from that of the endogenous ligand
(an "active site
") and enhances or inhibits the effects of the endogenous ligand. Under normal circumstances, it acts by causing a conformational change
in a receptor molecule, which results in a change in the binding affinity of the ligand. In this way, an allosteric ligand modulates the receptor's activation by its primary (orthosteric) ligand, and can be thought to act like a dimmer switch in an electrical circuit, adjusting the intensity of the response.
For example, the GABAA receptor has two active sites that the neurotransmitter gamma-aminobutyric acid
(GABA) binds, but also has benzodiazepine
and general anaesthetic agent
regulatory binding sites. These regulatory sites can each produce positive allosteric modulation, potentiating
the activity of GABA. Diazepam
is an agonist
at the benzodiazepine regulatory site, and its antidote flumazenil
is an antagonist
.
More recent examples of drugs that allosterically modulate their targets include the calcium-mimicking cinacalcet
and the HIV treatment maraviroc
.
(GPCR) allosteric binding sites have not faced the same evolutionary pressure as orthosteric sites to accommodate an endogenous ligand, so are more diverse. Therefore greater GPCR selectivity may be obtained by targeting allosteric sites. This is particularly useful for GPCRs where selective orthosteric therapy has been difficult because of sequence conservation of the orthosteric site across receptor subtypes.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. 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". 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.
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes...
, allosteric regulation is the regulation of an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
or other protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
by binding an effector
Effector (biology)
An effector is a molecule that binds to a protein and thereby alters the activity of that protein...
molecule at the protein's allosteric site (that is, a site other than the protein's active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
). 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. The term allostery comes from the Greek
Greek language
Greek is an independent branch of the Indo-European family of languages. Native to the southern Balkans, it has the longest documented history of any Indo-European language, spanning 34 centuries of written records. Its writing system has been the Greek alphabet for the majority of its history;...
allos (ἄλλος), "other", and stereos (στερεὀς), "solid (object)", in reference to the fact that the regulatory site of an allosteric protein is physically distinct from its active site. 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
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
.
Models of allosteric regulation
Most allosteric effects can be explained by the concerted MWC modelMWC model
In biochemistry, the MWC model describes allosteric transitions of proteins made up of identical subunits. It was proposed by Jean-Pierre Changeux based on his PhD experiments, and described by Jacques Monod, Jeffries Wyman, and Jean-Pierre Changeux...
put forth by Monod
Jacques Monod
Jacques Lucien Monod was a French biologist who was awarded a Nobel Prize in Physiology or Medicine in 1965, sharing it with François Jacob and Andre Lwoff "for their discoveries concerning genetic control of enzyme and virus synthesis"...
, Wyman, and Changeux
Jean-Pierre Changeux
Jean-Pierre Changeux is a French neuroscientist known for his research in several fields of biology, from the structure and function of proteins , to the early development of the nervous system up to cognitive functions...
, or by the sequential model
Sequential model
The sequential model is a theory that describes co-operativity of protein subunits.-Overview:This model suggests that the subunits of multimeric proteins have two conformational states. The binding of the ligand causes conformational change...
described by Koshland, Nemethy, and Filmer. Both postulate that enzyme subunit
Protein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...
s exist in one of two conformations
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
, tensed (T) or relaxed (R), and that relaxed subunits bind substrate more readily than those in the tense state. The two models differ most in their assumptions about subunit interaction and the preexistence of both states.
Concerted model
The concerted model of allostery, also referred to as the symmetry model or MWC modelMWC model
In biochemistry, the MWC model describes allosteric transitions of proteins made up of identical subunits. It was proposed by Jean-Pierre Changeux based on his PhD experiments, and described by Jacques Monod, Jeffries Wyman, and Jean-Pierre Changeux...
, postulates that enzyme subunits are connected in such a way that a conformational change in one subunit is necessarily conferred to all other subunits. Thus, all subunits must exist in the same conformation. The model further holds that, in the absence of any ligand (substrate or otherwise), the equilibrium favours one of the conformational states, T or R. The equilibrium can be shifted to the R or T state through the binding of one ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
(the allosteric effector or ligand) to a site that is different from the active site (the allosteric site).
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 substrate bind via an induced fit protocol. In general, when a subunit randomly collides with a molecule of substrateSubstrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
, the active site, in essence, forms a glove around its substrate. While such an induced fit converts a subunit from the tensed state to relaxed state, it does not propagate the conformational change to adjacent subunits. Instead, substrate-binding at one subunit only slightly alters the structure of other subunits so that their binding sites are more receptive to substrate. To summarize:
- subunits need not exist in the same conformation
- molecules of substrate bind via induced-fit protocol
- conformational changes are not propagated to all subunits
- substrate-binding causes increased substrate affinity in adjacent subunits.
Positive modulation
Positive allosteric modulation (also known as allosteric activation) occurs when the binding of one ligandLigand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
enhances the attraction between substrate molecules and other binding sites. An example is the binding of oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
molecules to hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
, where oxygen is effectively both the substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
and the effector. The allosteric, or "other", site is the active site of an adjoining protein subunit
Protein subunit
In structural biology, a protein subunit or subunit protein is a single protein molecule that assembles with other protein molecules to form a protein complex: a multimeric or oligomeric protein. Many naturally occurring proteins and enzymes are multimeric...
. The binding of oxygen to one subunit induces a conformational change in that subunit that interacts with the remaining active sites to enhance their oxygen affinity.
Negative modulation
Negative allosteric modulation (also known as allosteric inhibition) occurs when the binding of one ligandLigand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
decreases the affinity for substrate at other active sites. For example, when 2,3-BPG
2,3-Bisphosphoglycerate
2,3-Bisphosphoglyceric acid is a three-carbon isomer of the glycolytic intermediate 1,3-bisphosphoglyceric acid . 2,3-BPG is present in human red blood cells at approximately 5 mmol/L...
binds to an allosteric site on hemoglobin, the affinity for oxygen of all subunits decreases. This is when a regulator is absent from the binding site.
Another example is strychnine
Strychnine
Strychnine is a highly toxic , colorless crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine causes muscular convulsions and eventually death through asphyxia or sheer exhaustion...
, a convulsant
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
poison, which acts as an allosteric inhibitor of the glycine receptor
Glycine receptor
The glycine receptor, or GlyR, is the receptor for the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride current...
. Glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
is a major post-synaptic
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
inhibitory neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
in mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
ian spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
and brain stem
Brain stem
In vertebrate anatomy the brainstem is the posterior part of the brain, adjoining and structurally continuous with the spinal cord. The brain stem provides the main motor and sensory innervation to the face and neck via the cranial nerves...
. Strychnine acts at a separate binding site on the glycine receptor in an allosteric manner; i.e., its binding lowers the affinity of the glycine receptor for glycine. Thus, strychnine inhibits the action of an inhibitory transmitter, leading to convulsions.
Homotropic
A homotropic allosteric modulator is a substrateSubstrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
for its target enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
, as well as a regulatory molecule of the enzyme's activity. It is typically an activator of the enzyme.
Heterotropic
A heterotropic allosteric modulator is a regulatory molecule that is not also the enzyme's substrate. It may be either an activator or an inhibitor of the enzyme.Some allosteric proteins can be regulated by both their substrates and other molecules. Such proteins are capable of both homotropic and heterotropic interactions.
Non-regulatory allostery
A non-regulatory allosteric site refers to 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 "regulatory siteRegulatory site
A regulatory site is a site on an allosteric protein to which a modulator molecule binds. A ligand-binding site on a receptor or enzyme distinct from the active site. Allosteric modulators alter enzyme activity by binding to the regulatory site. Also known as an "allosteric site"....
") from that of the endogenous ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
(an "active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
") and enhances or inhibits the effects of the endogenous ligand. Under normal circumstances, it acts by causing a conformational change
Conformational change
A macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
in a receptor molecule, which results in a change in the binding affinity of the ligand. In this way, an allosteric ligand modulates the receptor's activation by its primary (orthosteric) ligand, and can be thought to act like a dimmer switch in an electrical circuit, adjusting the intensity of the response.
For example, the GABAA receptor has two active sites that the neurotransmitter gamma-aminobutyric acid
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
(GABA) binds, but also has benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
and general anaesthetic agent
General anaesthetic
A general anaesthetic is a drug that brings about a reversible loss of consciousness. These drugs are generally administered by an anaesthesia provider to induce or maintain general anaesthesia to facilitate surgery...
regulatory binding sites. These regulatory sites can each produce positive allosteric modulation, potentiating
Synergy
Synergy may be defined as two or more things functioning together to produce a result not independently obtainable.The term synergy comes from the Greek word from , , meaning "working together".-Definitions and usages:...
the activity of GABA. Diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
is an agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
at the benzodiazepine regulatory site, and its antidote flumazenil
Flumazenil
Flumazenil is a benzodiazepine antagonist available for injection only, and the only benzodiazepine receptor antagonist on the market today.It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by...
is an antagonist
Antagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
.
More recent examples of drugs that allosterically modulate their targets include the calcium-mimicking cinacalcet
Cinacalcet
Cinacalcet is a drug that acts as a calcimimetic by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues. It is sold by Amgen under the trade name Sensipar in North America and Australia and as Mimpara in Europe...
and the HIV treatment maraviroc
Maraviroc
Maraviroc is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection. It is also classed as an entry inhibitor.-Mechanism of action:...
.
Allosteric sites as drug targets
Allosteric sites may represent a novel drug target. There is a number of advantages in using allosteric modulators as preferred therapeutic agents over classic orthosteric ligands. For example, G protein-coupled receptorG protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
(GPCR) allosteric binding sites have not faced the same evolutionary pressure as orthosteric sites to accommodate an endogenous ligand, so are more diverse. Therefore greater GPCR selectivity may be obtained by targeting allosteric sites. This is particularly useful for GPCRs where selective orthosteric therapy has been difficult because of sequence conservation of the orthosteric site across receptor subtypes.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. 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". 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.
See also
- ASD databaseASD (database)AlloSteric Database is a database of allosteric molecules...
- Cooperative bindingCooperative bindingIn biochemistry, a macromolecule exhibits cooperative binding if its affinity for its ligand changes with the amount of ligand already bound.Cooperative binding is a special case of allostery. Cooperative binding requires that the macromolecule have more than one binding site, since cooperativity...
- Enzyme kineticsEnzyme kineticsEnzyme kinetics is the study of the chemical reactions that are catalysed by enzymes. In enzyme kinetics, the reaction rate is measured and the effects of varying the conditions of the reaction investigated...
- Protein dynamics
- Receptor theoryReceptor theoryReceptor theory is the application of receptor models to explain drug behaviour. Pharmacological receptor models preceded accurate knowledge of receptors by many years. John Newport Langley and Paul Ehrlich introduced the concept of a receptor that would mediate drug action at the beginning of the...
External links
- Instant insight introducing a classification system for protein allostery mechanisms from the Royal Society of ChemistryRoyal Society of ChemistryThe Royal Society of Chemistry is a learned society in the United Kingdom with the goal of "advancing the chemical sciences." It was formed in 1980 from the merger of the Chemical Society, the Royal Institute of Chemistry, the Faraday Society and the Society for Analytical Chemistry with a new...