In
biochemistryBiochemistry is the study of the chemical processes in living organisms. It deals with the structure and function of cellular components such as proteins, carbohydrates, lipids, nucleic acids and other biomolecules....
,
allosteric regulation is the regulation of an
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
or other
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
by binding an
effectorAn effector is a molecule that binds to a protein and thereby alters the activity of that protein. A modulator molecule binds to a regulatory site during allosteric modulation and allosterically modulates the shape of the protein.- Types of effectors :* Activators* Inhibitors....
molecule at the protein's allosteric site (that is, a site other than the protein's
active siteThe active site of an enzyme contains the catalytic and binding sites. The structure and chemical properties of the active site allow the recognition and binding of the substrate....
). 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
GreekGreek , an independent branch of the Indo-European family of languages, is the language of the Greeks. Native to the southern Balkans, it has the longest documented history of any Indo-European language, spanning 34 centuries of written records. In its ancient form, it is the language of classical...
allos, "other," and
stereos, "solid (object)," in reference to the fact that the regulatory site of an allosteric protein is physically distinct from its active site.
In
biochemistryBiochemistry is the study of the chemical processes in living organisms. It deals with the structure and function of cellular components such as proteins, carbohydrates, lipids, nucleic acids and other biomolecules....
,
allosteric regulation is the regulation of an
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
or other
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
by binding an
effectorAn effector is a molecule that binds to a protein and thereby alters the activity of that protein. A modulator molecule binds to a regulatory site during allosteric modulation and allosterically modulates the shape of the protein.- Types of effectors :* Activators* Inhibitors....
molecule at the protein's allosteric site (that is, a site other than the protein's
active siteThe active site of an enzyme contains the catalytic and binding sites. The structure and chemical properties of the active site allow the recognition and binding of the substrate....
). 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
GreekGreek , an independent branch of the Indo-European family of languages, is the language of the Greeks. Native to the southern Balkans, it has the longest documented history of any Indo-European language, spanning 34 centuries of written records. In its ancient form, it is the language of classical...
allos, "other," and
stereos, "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 natural example of control loops, such as feedback from downstream products or feedforward from upstream substrates.
Models of allosteric regulation
Most allosteric effects can be explained by the
concerted MWC modelIn 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
MonodSee also Jacques-Louis Monod, French-born composer and cousin of Jacques Monod.Jacques Lucien Monod was a French biologist who was awarded a Nobel Prize in Physiology or Medicine in 1965...
, Wyman, and
ChangeuxJean-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 modelThe sequential model is a theory that describes co-operativity of proteins 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
subunitIn 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
conformationConformation generally means structural arrangement.In science, it may refer to:*Chemical conformation, in chemistry, is the chemical structure of a molecule...
s, 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 modelIn 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 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
ligandIn biochemistry and pharmacology, a ligand is a substance that is able to bind to and form 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...
(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
substrateIn 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.
Activation
Allosteric activation, such as the binding of
oxygenOxygen Oxygen Oxygen (acid, literally "sharp", from the taste of acids) and -γενής (-genēs) (producer, literally begetter) is the element with atomic number 8 and represented by the symbol O...
molecules to
hemoglobinHemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of vertebrates, and the tissues of some invertebrates....
, occurs when the binding of one ligand enhances the attraction between substrate molecules and other binding sites. With respect to hemoglobin, oxygen is effectively both the
substrateIn 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 subunitIn 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.
Inhibition
Allosteric inhibition occurs when the binding of one
ligandIn chemistry, a ligand is either an atom, ion, or molecule that binds to a central metal-atom to produce a coordination complex. The bonding between the metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The metal-ligand bonding ranges from covalent...
decreases the affinity for substrate at other active sites. For example, when
2,3-BPG2,3-Bisphosphoglycerate is a three carbon isomer of the glycolytic intermediate 1,3-bisphosphoglycerate. 2,3-BPG is present in human red blood cells at approximately 5 mmol/L. It binds with greater affinity to deoxygenated hemoglobin 2,3-Bisphosphoglycerate (2,3-BPG, also known as...
binds to an allosteric site on hemoglobin, the affinity for oxygen of all subunits decreases.
http://template.bio.warwick.ac.uk/staff/dhodgson/dnacomp/boolean/allosteric.gif
Another example is
strychnineStrychnine is a very 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. The most common source is from the seeds of the...
, a
convulsantAn epileptic seizure is a transient symptom of excessive or synchronous neuronal activity in the brain. It can manifest as an alteration in mental state, tonic or clonic movements, convulsions, and various other psychic symptoms...
poison, which acts as an allosteric inhibitor of
glycineGlycine is an organic compound with the formula NH2CH2COOH. With only a hydrogen atom as its side chain, glycine is the smallest of the 20 amino acids commonly found in proteins....
. Glycine is a major post-synaptic inhibitory
neurotransmitterNeurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they...
in
mammalMammals are a class of vertebrate animals whose females are characterized by the possession of mammary glands while both males and females are characterized by sweat glands, hair, three middle ear bones used in hearing, and a neocortex region in the brain.Mammals are divided into three main...
ian
spinal cordThe 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. It is around 45 cm long in men and around 43 cm long in women. The length of the spinal cord is much shorter than...
and
brain stemThe brainstem is the lower 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 receptorThe glycine receptor, or GlyR, is the receptor for the amino acid neurotransmitter glycine. It is one of the most widely distributed inhibitory receptors in the central nervous system and has important roles in a variety of physiological processes, especially in mediating inhibitory...
in an allosteric manner; i.e. its binding lowers the
affinityAffinity, in etymology affinity is the opposite of infinity . These two words have the same root coming from the Latin: finis = end. “Affinity” meaning is near to the “finis” e.g...
of the glycine receptor for glycine. Strychnine, thus, inhibits the action of an inhibitory transmitter, causing convulsions.
Types of allosteric regulation: homotropic and heterotropic
Many allosteric enzymes are regulated by their
substrateIn 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...
; such a substrate is considered a
homotropic allosteric modulator, and is typically an activator. Non-substrate regulatory molecules are called
heterotropic allosteric modulators and can be either activators or inhibitors.
Some allosteric proteins can be regulated by their substrates and by other molecules, as well. Such proteins are capable of both homotropic and heterotropic interactions.
Pharmacology
Allosteric modulation of a receptor results from the binding of allosteric modulators at a different site (regulatory site) other than of the
endogenous ligandIn biochemistry and pharmacology, a ligand is a substance that is able to bind to and form 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...
(orthosteric ligand) and enhances or inhibits the effects of the endogenous ligand. It normally acts by causing a
conformational changeA 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” its activation by a primary “ligand” and can be thought to act like a dimmer switch in an electrical circuit, adjusting the intensity of the receptor’s activation.
The anti-anxiety drugs Valium, Xanax, Librium and Ativan, for example, “
potentiateSynergy is the term used to describe a situation where different entities cooperate advantageously for a final outcome. Simply defined, it means that the whole is greater than the sum of the individual parts. Although the whole will be greater than each individual part, this is not the concept of...
” or turn up the activity of the neurotransmitter gamma-aminobutyric acid (
GABAGabâ or gabaa, for the Cebuano people , is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
) when it binds to its primary ligand, the benzodiazepine receptor. More recent examples of drugs that allosterically modulate their drug targets include
CinacalcetCinacalcet 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
MaravirocMaraviroc is a drug used in the treatment of HIV infection.-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, 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
GPCRG 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...
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 is 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 cooperativity. An allosteric modulator may display neutral cooperativity 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.
External links
- Instant insight introducing a classification system for protein allostery mechanisms from the Royal Society of Chemistry
The Royal Society of Chemistry is a learned society in the United Kingdom with the goal of "advancing the chemical sciences." The organisation carries out research, publishes journals, books and databases, as well as hosting conferences, seminars and workshops...