Editing Allosteric regulation

{{Short description|Regulation of enzyme activity}}
{{use mdy dates|date=September 2021}}
{{Use American English|date = April 2019}}
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[[Image:Enzyme Model.svg|thumb|right|300px|Allosteric regulation of an enzyme]]

In the fields of [[biochemistry]] and [[pharmacology]] an '''allosteric regulator''' (or '''allosteric modulator''') is a substance that binds to a site on an [[enzyme]] or [[Receptor (biochemistry)|receptor]] distinct from the [[active site]], resulting in a conformational change that alters the protein's activity, either enhancing or inhibiting its function.  In contrast, substances that bind directly to an enzyme's active site or the binding site of the [[endogenous ligand]] of a receptor are called '''orthosteric''' regulators or modulators.

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]].<ref>{{cite journal | vauthors = Cooper A, Dryden DT | title = Allostery without conformational change. A plausible model | journal = European Biophysics Journal | volume = 11 | issue = 2 | pages = 103–109 | date = October 1984 | pmid = 6544679 | doi = 10.1007/BF00276625 | s2cid = 12591175 }}</ref><ref>{{cite journal | vauthors = Liu J, Nussinov R | title = Allostery: An Overview of Its History, Concepts, Methods, and Applications | journal = PLOS Computational Biology | volume = 12 | issue = 6 | pages = e1004966 | date = June 2016 | pmid = 27253437 | pmc = 4890769 | doi = 10.1371/journal.pcbi.1004966 | s2cid = 3610740 | doi-access = free | bibcode = 2016PLSCB..12E4966L }}</ref> 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#Biology|feedback]] from downstream products or [[Feed forward (control)|feedforward]] from upstream substrates. Long-range allostery is especially important in [[cell signaling]].<ref name="pmid21570668">{{cite book | vauthors = Bu Z, Callaway DJ | title = Protein Structure and Diseases | chapter = Proteins move! Protein dynamics and long-range allostery in cell signaling | volume = 83 | pages = 163–221 | year = 2011 | pmid = 21570668 | doi = 10.1016/B978-0-12-381262-9.00005-7 | isbn = 9780123812629 | series = Advances in Protein Chemistry and Structural Biology }}</ref> Allosteric regulation is also particularly important in the [[Cell (biology)|cell's]] ability to adjust [[enzyme]] activity.

The term ''allostery'' comes from the [[Ancient Greek]] ''allos'' ({{Wikt-lang|grc|ἄλλος}}), "other", and ''stereos'' ({{Wikt-lang|grc|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.  The term ''orthostery'' comes from the [[Ancient Greek]] orthós ({{Wikt-lang|grc|ὀρθός}}) meaning  “straight”, “upright”, “right” or “correct”.

== Ortho vs. allosteric inhibitors ==

=== Orthosteric ===

# Binding Site: Orthosteric inhibitors bind directly to the enzyme's active site, where the substrate normally binds.
# Mechanism of Action: By occupying the active site, these inhibitors prevent the substrate from binding, thereby directly blocking the enzyme's catalytic activity.
# Competitive Inhibition: Most orthosteric inhibitors compete with the substrate for the active site, which means their effectiveness can be reduced if substrate concentration increases.

=== Allosteric ===

# Binding Site: Allosteric inhibitors bind to a site on the enzyme that is distinct and separate from the active site, known as the allosteric site.
# Mechanism of Action: Binding to the allosteric site induces a conformational change in the enzyme that can either reduce the affinity of the active site for the substrate or alter the enzyme's catalytic activity. This indirect interference can inhibit the enzyme's function even if the substrate is present.
# Non-Competitive Inhibition: Allosteric inhibitors often exhibit non-competitive inhibition, meaning their inhibitory effect is not dependent on the substrate concentration.

== Models ==

[[File:Allosteric Regulation.svg|thumb|A – [[Active site]]<br/> B – Allosteric site<br/> C – [[Substrate (biochemistry)|Substrate]]<br/> D – [[Enzyme inhibitor|Inhibitor]]<br/> E – [[Enzyme]]<br/>This is a diagram of allosteric regulation of an enzyme.]]

Many allosteric effects can be explained by  the ''concerted'' [[MWC model]] put forth by [[Jacques Monod|Monod]], [[Jeffries Wyman (biologist)|Wyman]], and [[Jean-Pierre Changeux|Changeux]],<ref name="pmid14343300">{{cite journal | vauthors = Monod J, Wyman J, Changeux JP | title = On the nature of allosteric transitions:A plausible model | journal = Journal of Molecular Biology | volume = 12 | pages = 88–118 | date = May 1965 | pmid = 14343300 | doi = 10.1016/s0022-2836(65)80285-6}}</ref> or by the [[sequential model]] (also known as the KNF model) described by [[Daniel E. Koshland Jr.|Koshland]], Nemethy, and Filmer.<ref name="pmid5938952">{{cite journal | vauthors = Koshland DE, Némethy G, Filmer D | title = Comparison of experimental binding data and theoretical models in proteins containing subunits | journal = Biochemistry | volume = 5 | issue = 1 | pages = 365–85 | date = January 1966 | pmid = 5938952 | doi = 10.1021/bi00865a047}}</ref>  Both postulate that [[protein subunit]]s exist in one of two [[Protein structure|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 [[Protein subunit|subunit]]s exist in more than two [[Protein structure|conformations]], the allostery landscape model described by Cuendet, Weinstein, and LeVine,<ref name="Cuendet_2016">{{cite journal | vauthors = Cuendet MA, Weinstein H, LeVine MV | title = The Allostery Landscape: Quantifying Thermodynamic Couplings in Biomolecular Systems | journal = Journal of Chemical Theory and Computation | volume = 12 | issue = 12 | pages = 5758–5767 | date = December 2016 | pmid = 27766843 | pmc = 5156960 | doi = 10.1021/acs.jctc.6b00841 }}</ref> can be used. Allosteric regulation may be facilitated by the evolution of large-scale, low-energy conformational changes, which enables long-range allosteric interaction between distant binding sites.<ref>{{Cite journal | vauthors = Eckmann JP, Rougemont J, Tlusty T |date=2019-07-30 |title=Colloquium : Proteins: The physics of amorphous evolving matter |url=https://link.aps.org/doi/10.1103/RevModPhys.91.031001 |journal=Reviews of Modern Physics |language=en |volume=91 |issue=3 |pages=031001 |doi=10.1103/RevModPhys.91.031001 |arxiv=1907.13371 |bibcode=2019RvMP...91c1001E |s2cid=199001124 |issn=0034-6861}}</ref>

=== Concerted model ===

The  concerted model of allostery, also referred to as the symmetry model or [[MWC model]], 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 (biochemistry)|ligand]] (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]] 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]] model of allosteric regulation is a dissociative concerted model.<ref name=pmid16023348>{{cite journal | vauthors = Jaffe EK | title = Morpheeins--a new structural paradigm for allosteric regulation | journal = Trends in Biochemical Sciences | volume = 30 | issue = 9 | pages = 490–7 | date = September 2005 | pmid = 16023348 | doi = 10.1016/j.tibs.2005.07.003 }}</ref>

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]] (PBGS) is the prototype morpheein.

=== Ensemble models ===

Ensemble models of allosteric regulation enumerate an allosteric system's [[statistical ensemble]] as a function of its [[energy functional|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).<ref>{{cite journal | vauthors = Motlagh HN, Wrabl JO, Li J, Hilser VJ | title = The ensemble nature of allostery | journal = Nature | volume = 508 | issue = 7496 | pages = 331–9 | date = April 2014 | pmid = 24740064 | doi = 10.1038/nature13001 | pmc = 4224315 | bibcode = 2014Natur.508..331M }}</ref> Ensemble models like the ensemble allosteric model<ref>{{cite journal | vauthors = Hilser VJ, Wrabl JO, Motlagh HN | title = Structural and energetic basis of allostery | journal = Annual Review of Biophysics | volume = 41 | pages = 585–609 | year = 2012 | pmid = 22577828 | pmc = 3935618 | doi = 10.1146/annurev-biophys-050511-102319 }}</ref> and allosteric Ising model<ref>{{cite journal | vauthors = LeVine MV, Weinstein H | title = AIM for Allostery: Using the Ising Model to Understand Information Processing and Transmission in Allosteric Biomolecular Systems | journal = Entropy | volume = 17 | issue = 5 | pages = 2895–2918 | date = May 2015 | pmid = 26594108 | pmc = 4652859 | doi = 10.3390/e17052895 | bibcode = 2015Entrp..17.2895L | doi-access = free }}</ref>  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<ref name="Cuendet_2016"/>  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]] simulations can be used to estimate a system's statistical ensemble so that it can be analyzed with the allostery landscape model.

== Allosteric modulation ==
{{Main|Allosteric modulator}}
[[Allosteric modulation]] 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 (biology)|effector]] 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 inhibition|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.<ref>{{cite journal | vauthors = Abdel-Magid AF | title = Allosteric modulators: an emerging concept in drug discovery | journal = ACS Medicinal Chemistry Letters | volume = 6 | issue = 2 | pages = 104–7 | date = February 2015 | pmid = 25699154 | pmc = 4329591 | doi = 10.1021/ml5005365 }}</ref> In a biological system, allosteric modulation can be difficult to distinguish from modulation by [[substrate presentation]].

== Energy sensing model ==

An example of this model is seen with the ''[[Mycobacterium tuberculosis]]'', a [[bacteria|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 [[Adenosine monophosphate|AMP]] and [[Glucose 6-phosphate|G6P]]. Sites like these also serve as a sensing mechanism for the enzyme's performance.<ref name="pmid29215013">{{cite journal | vauthors = Zhong W, Cui L, Goh BC, Cai Q, Ho P, Chionh YH, Yuan M, Sahili AE, Fothergill-Gilmore LA, Walkinshaw MD, Lescar J, Dedon PC | title = Allosteric pyruvate kinase-based "logic gate" synergistically senses energy and sugar levels in Mycobacterium tuberculosis | journal = Nature Communications | volume = 8 | issue = 1 | pages = 1986 | date = December 2017 | pmid = 29215013 | pmc = 5719368 | doi = 10.1038/s41467-017-02086-y | bibcode = 2017NatCo...8.1986Z }}</ref>

=== Positive modulation ===

Positive allosteric modulation (also known as ''allosteric activation'') occurs when the binding of one [[ligand]] 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 (biochemistry)|substrate]] and the effector. The allosteric, or "other", site is the [[catalytic site|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.
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]] decreases the affinity for substrate at other active sites. For example, when [[2,3-bisphosphoglycerate|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. [[Direct thrombin inhibitors#Allosteric Inhibitors|Allosteric inhibitors]] of thrombin have been discovered that could potentially be used as anticoagulants.

Another example is [[strychnine]], a [[Seizure|convulsant]] poison, which acts as an allosteric inhibitor of the [[glycine receptor]]. [[Glycine]] is a major post-[[synapse|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 (pharmacology)|affinity]] 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 [[Adenosine triphosphate|ATP]] and the enzyme [[phosphofructokinase]] within the [[negative feedback]] loop that regulates [[glycolysis]].  Phosphofructokinase (generally referred to as [[PFK]]) is an enzyme that catalyses the third step of glycolysis: the [[phosphorylation]] of [[fructose-6-phosphate]] into [[fructose 1,6-bisphosphate]].  [[PFK]] can be allosterically inhibited by high levels of [[adenosine triphosphate|ATP]] within the cell.  When ATP levels are high, ATP will bind to an allosteric site on [[phosphofructokinase]], causing a change in the enzyme's three-dimensional shape.  This change causes its [[Affinity (pharmacology)|affinity]] for [[substrate (biochemistry)|substrate]] ([[fructose-6-phosphate]] and [[Adenosine triphosphate|ATP]]) at the active site to decrease, and the enzyme is deemed inactive.  This causes [[glycolysis]] to cease when ATP levels are high, thus conserving the body's [[glucose]] 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 (biochemistry)|substrate]] for its target [[protein]], as well as a regulatory molecule of the protein's activity.  It is typically an activator of the protein.<ref name="pmid24456211">{{cite journal | vauthors = Srinivasan B, Forouhar F, Shukla A, Sampangi C, Kulkarni S, Abashidze M, Seetharaman J, Lew S, Mao L, Acton TB, Xiao R, Everett JK, Montelione GT, Tong L, Balaram H | title = Allosteric regulation and substrate activation in cytosolic nucleotidase II from Legionella pneumophila | journal = The FEBS Journal | volume = 281 | issue = 6 | pages = 1613–1628 | date = March 2014 | pmid = 24456211 | pmc = 3982195 | doi = 10.1111/febs.12727 }}</ref> For example, O<sub>2</sub> 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.<ref name="pmid24456211" />

=== 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<sup>+</sup>, CO<sub>2</sub>, and [[2,3-bisphosphoglycerate]] are heterotropic allosteric modulators of hemoglobin.<ref>{{cite journal | vauthors = Edelstein SJ | title = Cooperative interactions of hemoglobin | journal = Annual Review of Biochemistry | volume = 44 | pages = 209–32 | year = 1975 | pmid = 237460 | doi = 10.1146/annurev.bi.44.070175.001233 }}</ref> 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.<ref name="pmid24456211" />

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.<ref name="pmid24456211" />

=== {{anchor|Essential Activators}}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.<ref>{{cite journal | vauthors = Shi D, Allewell NM, Tuchman M | title = The N-Acetylglutamate Synthase Family: Structures, Function and Mechanisms | journal = International Journal of Molecular Sciences | volume = 16 | issue = 6 | pages = 13004–22 | date = June 2015 | pmid = 26068232 | pmc = 4490483 | doi = 10.3390/ijms160613004 | doi-access = free }}</ref><ref>{{cite journal | vauthors = de Cima S, Polo LM, Díez-Fernández C, Martínez AI, Cervera J, Fita I, Rubio V | title = Structure of human carbamoyl phosphate synthetase: deciphering the on/off switch of human ureagenesis | journal = Scientific Reports | volume = 5 | issue = 1 | pages = 16950 | date = November 2015 | pmid = 26592762 | pmc = 4655335 | doi = 10.1038/srep16950 | bibcode = 2015NatSR...516950D }}</ref>

== 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]]") from that of the [[Ligand (biochemistry)|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 [[Dissociation constant#Protein-ligand binding|binding affinity]] of the ligand. In this way, an allosteric ligand modulates the receptor's activation by its primary [[wikt:orthosteric|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|GABA<sub>A</sub> receptor]] has two active sites that the neurotransmitter [[gamma-aminobutyric acid]] (GABA) binds, but also has [[benzodiazepine]] and [[general anaesthetic|general anaesthetic agent]] regulatory binding sites. These regulatory sites can each produce positive allosteric modulation, [[Synergy|potentiating]] the activity of GABA. [[Diazepam]] is a [[agonist|positive allosteric modulator]] at the benzodiazepine regulatory site, and its antidote [[flumazenil]] is a [[receptor antagonist]].

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,<ref name=NC>{{cite journal | vauthors = Nussinov R, Tsai C | title = Allostery in disease and in drug discovery | journal = Cell | volume = 153 | pages = 293–305 | year = 2013 | issue = 2 | pmid = 23582321 | doi = 10.1016/j.cell.2013.03.034 | doi-access = free }}</ref><ref name=AAI>{{cite journal | vauthors = Abrusan G, Ascher DB, Inouye M | title = Known allosteric proteins have central roles in genetic disease | journal = PLOS Computational Biology | volume = 18 | pages = e1009806 | year = 2022 | issue = 2 | pmid = 10138267 | doi =  10.1371/journal.pcbi.1009806 | doi-access = free | arxiv = 2107.04318 | bibcode = 2022PLSCB..18E9806A }}</ref> and allosteric sites may represent a novel [[Drug discovery#Targets|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.<ref name=AC>{{cite journal | vauthors = Christopoulos A, May LT, Avlani VA, Sexton PM | title = G-protein-coupled receptor allosterism: the promise and the problem(s) | journal = Biochemical Society Transactions | volume = 32 | issue = Pt 5 | pages = 873–7 | date = November 2004 | pmid = 15494038 | doi = 10.1042/BST0320873 }}</ref> Therefore, greater GPCR selectivity may be obtained by targeting allosteric sites.<ref name=AC/> This is particularly useful for GPCRs where selective orthosteric therapy has been difficult because of sequence conservation of the orthosteric site across receptor subtypes.<ref name=LM>{{cite journal | vauthors = May LT, Leach K, Sexton PM, Christopoulos A | title = Allosteric modulation of G protein-coupled receptors | journal = Annual Review of Pharmacology and Toxicology | volume = 47 | pages = 1–51 | year = 2007 | pmid = 17009927 | doi = 10.1146/annurev.pharmtox.47.120505.105159 }}</ref> 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.<ref name=AC/> 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".<ref name=LM/> 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.<ref name=LM/>  Oligomer-specific small molecule binding sites are drug targets for medically relevant [[morpheein]]s.<ref name=pmid21643557>{{cite journal | vauthors = Jaffe EK | title = Morpheeins – A New Pathway for Allosteric Drug Discovery~!2010-02-12~!2010-05-21~!2010-06-08~! | journal = The Open Conference Proceedings Journal | volume = 1 | pages = 1–6 | year = 2010 | pmid = 21643557 | pmc = 3107518 | doi =  10.2174/2210289201001010001  |doi-access=free}}</ref>

== Synthetic allosteric systems ==
There are many synthetic compounds containing several [[noncovalent]] binding sites, which exhibit conformational changes upon occupation of one site. Cooperativity between single binding contributions in such [[supramolecular]] 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.<ref>{{cite journal | vauthors = Takeuchi M, Ikeda M, Sugasaki A, Shinkai S | title = Molecular design of artificial molecular and ion recognition systems with allosteric guest responses | journal = Accounts of Chemical Research | volume = 34 | issue = 11 | pages = 865–73 | date = November 2001 | pmid = 11714258 | doi = 10.1021/ar0000410 }}</ref><ref>{{cite journal | vauthors = Kremer C, Lützen A | title = Artificial allosteric receptors | journal = Chemistry: A European Journal | volume = 19 | issue = 20 | pages = 6162–96 | date = May 2013 | pmid = 23463705 | doi = 10.1002/chem.201203814 }}</ref><ref>{{cite journal | vauthors = Kovbasyuk L, Krämer R | title = Allosteric supramolecular receptors and catalysts | journal = Chemical Reviews | volume = 104 | issue = 6 | pages = 3161–87 | date = June 2004 | pmid = 15186190 | doi = 10.1021/cr030673a }}</ref> 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.<ref>{{cite journal | vauthors = Schneider HJ | title = Efficiency parameters in artificial allosteric systems | journal = Organic & Biomolecular Chemistry | volume = 14 | issue = 34 | pages = 7994–8001 | date = September 2016 | pmid = 27431438 | doi = 10.1039/c6ob01303a }}</ref>

In many multivalent [[supramolecular]] systems<ref>{{cite journal | vauthors = Badjić JD, Nelson A, Cantrill SJ, Turnbull WB, Stoddart JF | title = Multivalency and cooperativity in supramolecular chemistry | journal = Accounts of Chemical Research | volume = 38 | issue = 9 | pages = 723–32 | date = September 2005 | pmid = 16171315 | doi = 10.1021/ar040223k }}</ref> 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.<ref>{{cite journal | vauthors = Kim SK, Sessler JL | title = Ion pair receptors | journal = Chemical Society Reviews | volume = 39 | issue = 10 | pages = 3784–809 | date = October 2010 | pmid = 20737073 | doi = 10.1039/c002694h | pmc = 3016456 }}</ref><ref>{{cite journal | vauthors = McConnell AJ, Beer PD | title = Heteroditopic receptors for ion-pair recognition | journal = Angewandte Chemie | volume = 51 | issue = 21 | pages = 5052–61 | date = May 2012 | pmid = 22419667 | doi = 10.1002/anie.201107244 }}</ref> This cooperativity 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. [http://mdl.shsmu.edu.cn/ASD The AlloSteric Database] (ASD)<ref name=ZH>{{cite journal | vauthors = Huang Z, Zhu L, Cao Y, Wu G, Liu X, Chen Y, Wang Q, Shi T, Zhao Y, Wang Y, Li W, Li Y, Chen H, Chen G, Zhang J | title = ASD: a comprehensive database of allosteric proteins and modulators | journal = Nucleic Acids Research | volume = 39 | issue = Database issue | pages = D663–9 | date = January 2011 | pmid = 21051350 | pmc = 3013650 | doi = 10.1093/nar/gkq1022 }}</ref> 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.<ref>{{cite journal | vauthors = Panjkovich A, Daura X | title = Exploiting protein flexibility to predict the location of allosteric sites | journal = BMC Bioinformatics | volume = 13 | pages = 273 | date = October 2012 | pmid = 23095452 | pmc = 3562710 | doi = 10.1186/1471-2105-13-273 |doi-access=free }}</ref><ref>{{cite journal | vauthors = Süel GM, Lockless SW, Wall MA, Ranganathan R | title = Evolutionarily conserved networks of residues mediate allosteric communication in proteins | journal = Nature Structural Biology | volume = 10 | issue = 1 | pages = 59–69 | date = January 2003 | pmid = 12483203 | doi = 10.1038/nsb881 | s2cid = 67749580 }}</ref><ref>{{cite journal | vauthors = Mitternacht S, Berezovsky IN | title = Binding leverage as a molecular basis for allosteric regulation | journal = PLOS Computational Biology | volume = 7 | issue = 9 | pages = e1002148 | date = September 2011 | pmid = 21935347 | pmc = 3174156 | doi = 10.1371/journal.pcbi.1002148 |doi-access=free | bibcode = 2011PLSCB...7E2148M }}</ref><ref>{{cite journal | vauthors = Gasper PM, Fuglestad B, Komives EA, Markwick PR, McCammon JA | title = Allosteric networks in thrombin distinguish procoagulant vs. anticoagulant activities | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 52 | pages = 21216–22 | date = December 2012 | pmid = 23197839 | pmc = 3535651 | doi = 10.1073/pnas.1218414109 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ghosh A, Vishveshwara S | title = Variations in clique and community patterns in protein structures during allosteric communication: investigation of dynamically equilibrated structures of methionyl tRNA synthetase complexes | journal = Biochemistry | volume = 47 | issue = 44 | pages = 11398–407 | date = November 2008 | pmid = 18842003 | doi = 10.1021/bi8007559 }}</ref><ref>{{cite journal | vauthors = Sethi A, Eargle J, Black AA, Luthey-Schulten Z | title = Dynamical networks in tRNA:protein complexes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 16 | pages = 6620–5 | date = April 2009 | pmid = 19351898 | pmc = 2672494 | doi = 10.1073/pnas.0810961106 | bibcode = 2009PNAS..106.6620S | doi-access = free }}</ref><ref>{{cite journal | vauthors = Vanwart AT, Eargle J, Luthey-Schulten Z, Amaro RE | title = Exploring residue component contributions to dynamical network models of allostery | journal = Journal of Chemical Theory and Computation | volume = 8 | issue = 8 | pages = 2949–2961 | date = August 2012 | pmid = 23139645 | pmc = 3489502 | doi = 10.1021/ct300377a }}</ref><ref>{{cite journal | vauthors = Rivalta I, Sultan MM, Lee NS, Manley GA, Loria JP, Batista VS | title = Allosteric pathways in imidazole glycerol phosphate synthase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 22 | pages = E1428–36 | date = May 2012 | pmid = 22586084 | pmc = 3365145 | doi = 10.1073/pnas.1120536109 | doi-access = free }}</ref> In part, this growing interest is a result of their general importance in protein science, but also because allosteric residues may be exploited in [[#Allosteric sites as drug targets|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.<ref name="pmid30530700">{{cite journal | vauthors = Negre CF, Morzan UN, Hendrickson HP, Pal R, Lisi GP, Loria JP, Rivalta I, Ho J, Batista VS | title = Eigenvector centrality for characterization of protein allosteric pathways | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 115 | issue = 52 | pages = E12201–E12208 | date = December 2018 | pmid = 30530700 | pmc = 6310864 | doi = 10.1073/pnas.1810452115 | arxiv = 1706.02327 | bibcode = 2018PNAS..11512201N | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Clarke D, Sethi A, Li S, Kumar S, Chang RW, Chen J, Gerstein M | title = Identifying Allosteric Hotspots with Dynamics: Application to Inter- and Intra-species Conservation | journal = Structure | volume = 24 | issue = 5 | pages = 826–837 | date = May 2016 | pmid = 27066750 | pmc = 4883016 | doi = 10.1016/j.str.2016.03.008 }}</ref><ref>{{cite journal | vauthors = Dutta S, Eckmann JP, Libchaber A, Tlusty T | title = Green function of correlated genes in a minimal mechanical model of protein evolution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 115 | issue = 20 | pages = E4559–E4568 | date = May 2018 | pmid = 29712824 | pmc = 5960285 | doi = 10.1073/pnas.1716215115 | arxiv = 1801.03681 | bibcode = 2018PNAS..115E4559D | doi-access = free }}</ref>

== See also ==
* [[ASD (database)|ASD database]]
* [[Anharmonicity]]
* [[Competitive inhibition]]
* [[Cooperative binding]]
* [[Enzyme kinetics]]
* [[Protein dynamics]]
* [[Receptor theory]]

== References ==

{{reflist|2}}

== External links ==
{{wiktionary | allosteric}}
*[http://www.rsc.org/Publishing/Journals/cb/Volume/2009/3/sorting_perturbed_proteins.asp Instant insight] introducing a classification system for protein allostery mechanisms from the [[Royal Society of Chemistry]]

{{Enzymes}}

[[Category:Proteins]]
[[Category:Enzyme kinetics]]