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In
biochemistry Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
, allosteric regulation (or allosteric control) is the regulation of an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...
by binding an effector molecule at a site other than the enzyme's
active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding 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 In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or othe ...
and/or a change in
protein dynamics Proteins are generally thought to adopt unique structures determined by their amino acid sequences. However, proteins are not strictly static objects, but rather populate ensembles of (sometimes similar) conformations. Transitions between these sta ...
. 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 Feedback occurs when outputs of a system are routed back as inputs as part of a chain of cause-and-effect that forms a circuit or loop. The system can then be said to ''feed back'' into itself. The notion of cause-and-effect has to be handled c ...
from downstream products or
feedforward Feedforward is the provision of context of what one wants to communicate prior to that communication. In purposeful activity, feedforward creates an expectation which the actor anticipates. When expected experience occurs, this provides confirmato ...
from upstream substrates. Long-range allostery is especially important in
cell signaling In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
. Allosteric regulation is also particularly important in the cell's ability to adjust
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...
activity. The term ''allostery'' comes from the Ancient Greek ''allos'' (), "other", and ''stereos'' (), "solid (object)". This is in reference to the fact that the regulatory site of an allosteric protein is physically distinct from its active site.


Models

Many allosteric effects can be explained by the ''concerted''
MWC model In biochemistry, the Monod-Wyman-Changeux model (MWC model, also known as the symmetry model) describes allosteric transitions of proteins made up of identical subunits. It was proposed by Jean-Pierre Changeux in his PhD thesis, and described by J ...
put forth by Monod, Wyman, and Changeux, or by the
sequential model The sequential model (also known as the KNF model) is a theory that describes cooperativity of protein subunits. Koshland, D.E., Némethy, G. and Filmer, D. (1966) Comparison of experimental binding data and theoretical models in proteins contain ...
(also known as the KNF model) described by Koshland, Nemethy, and Filmer. Both postulate that
protein subunit In structural biology, a protein subunit is a polypeptide chain or single protein molecule that assembles (or "''coassembles''") with others to form a protein complex. Large assemblies of proteins such as viruses often use a small number of t ...
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. For proteins in which subunits exist in more than two conformations, the allostery landscape model described by Cuendet, Weinstein, and LeVine, can be used.


Concerted model

The concerted model of allostery, also referred to as the symmetry model or
MWC model In biochemistry, the Monod-Wyman-Changeux model (MWC model, also known as the symmetry model) describes allosteric transitions of proteins made up of identical subunits. It was proposed by Jean-Pierre Changeux in his PhD thesis, and described by J ...
, 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 favors 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 In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
(the allosteric effector or ligand) to a site that is different from the active 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 a substrate bind via an
induced fit Enzyme catalysis is the increase in the rate of a process by a biological molecule, an "enzyme". Most enzymes are proteins, and most such processes are chemical reactions. Within the enzyme, generally catalysis occurs at a localized site, called ...
protocol. 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


Morpheein model

The
morpheein Morpheeins are proteins that can form two or more different homo-oligomers (morpheein forms), but must come apart and change shape to convert between forms. The alternate shape may reassemble to a different oligomer. The shape of the subunit ...
model of allosteric regulation is a dissociative concerted model. 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.
Porphobilinogen synthase Aminolevulinic acid dehydratase (porphobilinogen synthase, or ALA dehydratase, or aminolevulinate dehydratase) is an enzyme () that in humans is encoded by the ''ALAD'' gene. Porphobilinogen synthase (or ALA dehydratase, or aminolevulinate de ...
(PBGS) is the prototype morpheein.


Ensemble models

Ensemble models of allosteric regulation enumerate an allosteric system's
statistical ensemble In physics, specifically statistical mechanics, an ensemble (also statistical ensemble) is an idealization consisting of a large number of virtual copies (sometimes infinitely many) of a system, considered all at once, each of which represents a ...
as a function of its potential energy function, and then relate specific statistical measurements of allostery to specific energy terms in the energy function (such as an intermolecular salt bridge between two domains). Ensemble models like the ensemble allosteric model and allosteric Ising model assume that each domain of the system can adopt two states similar to the MWC model. The allostery landscape model introduced by Cuendet, Weinstein, and LeVine allows for the domains to have any number of states and the contribution of a specific molecular interaction to a given allosteric coupling can be estimated using a rigorous set of rules.
Molecular dynamics Molecular dynamics (MD) is a computer simulation method for analyzing the physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a fixed period of time, giving a view of the dynamic "evolution" of the s ...
simulations can be used to estimate a system's statistical ensemble so that it can be analyzed with the allostery landscape model.


Allosteric modulation

Allosteric modulation In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to ...
is used to alter the activity of molecules and enzymes in biochemistry and pharmacology. For comparison, a typical drug is made to bind to the active site of an enzyme which thus prohibits binding of a substrate to that enzyme causing a decrease in enzyme activity. Allosteric modulation occurs when an
effector Effector may refer to: *Effector (biology), a molecule that binds to a protein and thereby alters the activity of that protein * ''Effector'' (album), a music album by the Experimental Techno group Download * ''EFFector'', a publication of the El ...
binds to an allosteric site (also known as a regulatory site) of an enzyme and alters the enzyme activity. Allosteric modulators are designed to fit the allosteric site to cause a conformational change of the enzyme, in particular a change in the shape of the active site, which then causes a change in its activity. In contrast to typical drugs, modulators are not competitive inhibitors. They can be positive (activating) causing an increase of the enzyme activity or negative (inhibiting) causing a decrease of the enzyme activity. The use of allosteric modulation allows the control of the effects of specific enzyme activities; as a result, allosteric modulators are very effective in pharmacology. In a biological system, allosteric modulation can be difficult to distinguish from modulation by
substrate presentation Substrate presentation is a biological process that activates a protein. The protein is sequestered away from its substrate and then activated by release and exposure of the protein to its substrate. A substrate is typically the substance on which ...
.


Energy sensing model

An example of this model is seen with the ''
Mycobacterium tuberculosis ''Mycobacterium tuberculosis'' (M. tb) is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, ''M. tuberculosis'' has an unusual, waxy coating on its ...
'', a
bacterium Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
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.


Positive modulation

Positive allosteric modulation (also known as ''allosteric activation'') occurs when the binding of one
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
enhances the attraction between substrate molecules and other binding sites. An example is the binding of
oxygen Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as well ...
molecules to
hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyt ...
, where oxygen is effectively both the substrate and the effector. The allosteric, or "other", site is the
active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) ...
of an adjoining
protein subunit In structural biology, a protein subunit is a polypeptide chain or single protein molecule that assembles (or "''coassembles''") with others to form a protein complex. Large assemblies of proteins such as viruses often use a small number of t ...
. 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. Another example of allosteric activation is seen in cytosolic IMP-GMP specific 5'-nucleotidase II (cN-II), where the affinity for substrate GMP increases upon GTP binding at the dimer interface.


Negative modulation

Negative allosteric modulation (also known as ''allosteric inhibition'') occurs when the binding of one
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
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. Direct thrombin inhibitors provides an excellent example of negative allosteric modulation. Allosteric inhibitors of thrombin have been discovered that could potentially be used as anticoagulants. Another example is
strychnine Strychnine (, , US chiefly ) is a highly toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, or absorbed through the e ...
, a convulsant poison, which acts as an allosteric inhibitor of the
glycine receptor The glycine receptor (abbreviated as GlyR or GLR) is the receptor of the amino acid neurotransmitter glycine. GlyR is an ionotropic receptor that produces its effects through chloride current. It is one of the most widely distributed inhibitory ...
.
Glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogen ...
is a major post- synaptic inhibitory
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotr ...
in
mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
ian
spinal cord The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spin ...
and
brain stem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is conti ...
. Strychnine acts at a separate binding site on the glycine receptor in an allosteric manner; i.e., its binding lowers the
affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...
of the glycine receptor for glycine. Thus, strychnine inhibits the action of an inhibitory transmitter, leading to convulsions. Another instance in which negative allosteric modulation can be seen is between ATP and the enzyme
phosphofructokinase Phosphofructokinase (PFK) is a kinase enzyme that phosphorylates fructose 6-phosphate in glycolysis. Function The enzyme-catalysed transfer of a phosphoryl group from ATP is an important reaction in a wide variety of biological processes. P ...
within the
negative feedback Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...
loop that regulates
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH) ...
. Phosphofructokinase (generally referred to as PFK) is an enzyme that catalyses the third step of glycolysis: the
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of
fructose-6-phosphate Fructose 6-phosphate (sometimes called the Neuberg ester) is a derivative of fructose, which has been phosphorylated at the 6-hydroxy group. It is one of several possible fructosephosphates. The β-D-form of this compound is very common in cells. ...
into
fructose 1,6-bisphosphate Fructose 1,6-bisphosphate, also known as Harden-Young ester, is fructose sugar phosphorylated on carbons 1 and 6 (i.e., is a fructosephosphate). The β-D-form of this compound is common in cells. Upon entering the cell, most glucose and fructose ...
. PFK can be allosterically inhibited by high levels of ATP within the cell. When ATP levels are high, ATP will bind to an allosteric site on
phosphofructokinase Phosphofructokinase (PFK) is a kinase enzyme that phosphorylates fructose 6-phosphate in glycolysis. Function The enzyme-catalysed transfer of a phosphoryl group from ATP is an important reaction in a wide variety of biological processes. P ...
, causing a change in the enzyme's three-dimensional shape. This change causes its
affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...
for substrate (
fructose-6-phosphate Fructose 6-phosphate (sometimes called the Neuberg ester) is a derivative of fructose, which has been phosphorylated at the 6-hydroxy group. It is one of several possible fructosephosphates. The β-D-form of this compound is very common in cells. ...
and ATP) at the active site to decrease, and the enzyme is deemed inactive. This causes
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH) ...
to cease when ATP levels are high, thus conserving the body's
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
and maintaining balanced levels of cellular ATP. In this way, ATP serves as a negative allosteric modulator for PFK, despite the fact that it is also a substrate of the enzyme.


Types


Homotropic

A homotropic allosteric modulator is a substrate for its target protein, as well as a regulatory molecule of the protein's activity. It is typically an activator of the protein. For example, O2 and CO are homotropic allosteric modulators of hemoglobin. Likewise, in IMP/GMP specific 5' nucleotidase, binding of one GMP molecule to a single subunit of the tetrameric enzyme leads to increased affinity for GMP by the subsequent subunits as revealed by sigmoidal substrate versus velocity plots.


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 2,3-bisphosphoglycerate are heterotropic allosteric modulators of hemoglobin. Once again, in IMP/GMP specific 5' nucleotidase, binding of GTP molecule at the dimer interface in the tetrameric enzyme leads to increased affinity for substrate GMP at the active site indicating towards K-type heterotropic allosteric activation. 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.


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.


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 "
regulatory site 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 ...
") from that of the endogenous ligand (an "
active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate (binding site) ...
") and enhances or inhibits the effects of the endogenous ligand. Under normal circumstances, it acts by causing a
conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or othe ...
in a receptor molecule, which results in a change in the
binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mole ...
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 Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, i ...
and general anaesthetic agent regulatory binding sites. These regulatory sites can each produce positive allosteric modulation, potentiating the activity of GABA.
Diazepam Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, ...
is a
positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds t ...
at the benzodiazepine regulatory site, and its antidote
flumazenil Flumazenil (also known as flumazepil, code name Ro 15-1788) is a selective GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines ( ...
is an
receptor antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...
. More recent examples of drugs that allosterically modulate their targets include the calcium-mimicking
cinacalcet Cinacalcet, sold under the brand name Sensipar among others, is a medication used to treat tertiary hyperparathyroidism, parathyroid carcinoma, and primary hyperparathyroidism. Text was copied from this source which is © European Medicines Agenc ...
and the HIV treatment
maraviroc Maraviroc, sold under the brand names Selzentry (US) and Celsentri (EU), is an antiretroviral medication used to treat HIV infection. It is taken by mouth. It is in the CCR5 receptor antagonist class. It was approved for medical use in the Uni ...
.


Allosteric sites as drug targets

Allosteric sites may represent a novel
drug target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
. There are a number of advantages in using allosteric modulators as preferred therapeutic agents over classic orthosteric ligands. For example,
G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
(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. Oligomer-specific small molecule binding sites are drug targets for medically relevant
morpheein Morpheeins are proteins that can form two or more different homo-oligomers (morpheein forms), but must come apart and change shape to convert between forms. The alternate shape may reassemble to a different oligomer. The shape of the subunit ...
s.


Synthetic allosteric systems

There are many synthetic compounds containing several
noncovalent In chemistry, a non-covalent interaction differs from a covalent bond in that it does not involve the sharing of electrons, but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. The ...
binding sites, which exhibit conformational changes upon occupation of one site. Cooperativity between single binding contributions in such
supramolecular Supramolecular chemistry refers to the branch of chemistry concerning chemical systems composed of a discrete number of molecules. The strength of the forces responsible for spatial organization of the system range from weak intermolecular forces, ...
systems is positive if occupation of one binding site enhances the affinity Δ''G'' at a second site, and negative if the affinity isn't highered. Most synthetic allosteric complexes rely on conformational reorganization upon the binding of one effector ligand which then leads to either enhanced or weakened association of second ligand at another binding site. Conformational coupling between several binding sites is in artificial systems usually much larger than in proteins with their usually larger flexibility. The parameter which determines the efficiency (as measured by the ratio of equilibrium constants Krel = KA(E)/KA in presence and absence of an effector E ) is the conformational energy needed to adopt a closed or strained conformation for the binding of a ligand A. In many multivalent
supramolecular Supramolecular chemistry refers to the branch of chemistry concerning chemical systems composed of a discrete number of molecules. The strength of the forces responsible for spatial organization of the system range from weak intermolecular forces, ...
systems direct interaction between bound ligands can occur, which can lead to large cooperativities. Most common is such a direct interaction between ions in receptors for ion-pairs. This cooperatitiy is often also referred to as allostery, even though conformational changes here are not necessarily triggering binding events.


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) 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. 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. 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.


See also

* ASD database *
Competitive inhibition Competitive inhibition is interruption of a chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for binding or bonding. Any metabolic or chemical messenger system can potentially be affected ...
*
Cooperative binding Molecular binding is an interaction between molecules that results in a stable physical association between those molecules. Cooperative binding occurs in binding systems containing more than one type, or species, of molecule and in which one of t ...
*
Enzyme kinetics Enzyme kinetics is the study of the rates of enzyme-catalysed chemical reactions. In enzyme kinetics, the reaction rate is measured and the effects of varying the conditions of the reaction are investigated. Studying an enzyme's kinetics in th ...
*
Protein dynamics Proteins are generally thought to adopt unique structures determined by their amino acid sequences. However, proteins are not strictly static objects, but rather populate ensembles of (sometimes similar) conformations. Transitions between these sta ...
*
Receptor theory Receptor theory is the application of receptor models to explain drug behavior. Pharmacological receptor models preceded accurate knowledge of receptors by many years. John Newport Langley and Paul Ehrlich introduced the concept of a receptor that ...


References


External links


Instant insight
introducing a classification system for protein allostery mechanisms from the
Royal Society of Chemistry The Royal Society of Chemistry (RSC) is a learned society ( professional association) in the United Kingdom with the goal of "advancing the chemical sciences". It was formed in 1980 from the amalgamation of the Chemical Society, the Royal Instit ...
{{Enzymes Proteins Enzyme kinetics