E-Mail Alert

Add your e-mail address to receive forthcoming issues of this journal:

Journal Browser

Journal Browser

Special Issue "Allosteric Modulation"

Quicklinks

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (30 June 2010)

Special Issue Editors

Guest Editor
Prof. Dr. Paolo Ascenzi

Dipartimento di Biologia, Università Roma Tre, Viale Marconi 446, 00146 Roma, Italy
E-Mail
Fax: +39 06 57336321
Guest Editor
Prof. Dr. Massimo Coletta

Department of Experimental Medicine and Biochemical Sciences, University of Roma Tor Vergata, Via Montpellier 1, I-00133 Roma, Italy
E-Mail

Special Issue Information

Dear Colleagues,

The term allostery comes from the Greek allos, “other”, and stereos, “solid (object)”, in reference to the phenomenon, occurring in several biological macromolecules, wherefore the affinity of an exogenous molecule (ligand 1) for the active site of the macromolecule (site 1) is affected by the interaction of a second molecule (ligand 2) at a site topologically distinct from the active site (site 2).

This concept was first introduced by Monod, Changeux and Jacob (Monod, J., Changeux, J.-P., and Jacob, F. (1963) Allosteric proteins and cellular control systems. J. Mol. Biol. 6, 306-329) and it was further clarified in a subsequent fundamental paper (Monod, J., Wyman, J., and Changeux, J.-P. (1965) On the nature of allosteric transitions: a plausible model. J. Mol. Biol. 12, 88-118), where the allosteric mechanism has been splitted in:

(i) homotropic allosteric interaction when ligand 1 and ligand 2 are the same type of molecule and site 1 and site 2, though topologically distinct, exert the same functional activity;

(ii) heterotropic allosteric interaction when ligand 1 and ligand 2 are different molecules and site 1 and site 2 display a different functional activity. In this case, ligand 2 is called effector and site 2 is called regulatory site.

The most widely known example of an allosteric protein is represented by hemoglobin (Hb), which shows both types of allostery, namely (a) the homotropic interaction among the four molecules of dioxygen binding to the four hemes, giving rise to cooperativity, and (b) the heterotropic interaction between dioxygen binding to the heme and effector molecules, such as 2,3-BPG (which binds at a crevice between the two β-chains) and H+ (which protonate several groups functionally relevant). Obviously, homotropic allosteric interactions are only possible for macromolecules displaying multiple active sites, whereas heterotropic allosteric interactions may occur also in macromolecules with only one site 1 and one site 2.

Allosteric interactions may have either activating or inhibitory effects according to whether the presence of ligand 2 on site 2 increases or decreases, respectively, the affinity of ligand 1 for site 1. Energy conservation law demands that the affinity effect is reciprocal for the two interacting sites (that is the effect on the affinity of ligand 2 for site 2 is quantitatively identical when ligand 1 is bound to site 1); the binding free energy difference is called interaction energy.

All dynamic proteins are potentially allosteric and allostery plays crucial roles in all cellular pathways. Furthermore, allosteric interactions may represent a mechanism of the utmost importance for the regulation of drug action and their characterization is a crucial step for determining the selectivity of the drug activity. Therefore, allosteric sites must be considered as selective drug targets, showing several advantages over the active center(s). As a matter of fact, since allosteric binding sites could be faced to a higher evolutionary pressure than active center(s), the use of drugs as allosteric effectors should foresee a decreased potential toxic effects, as “allosteric” drugs could be administrated at a lower dosage (i.e., in a sub-stoichiometric ratio) than drugs targeting directly the active center(s). Another type of pharmacological selectivity that is unique to allosteric modulators is based on cooperativity. Indeed, an allosteric modulator may display cooperativity by binding to a single member of a protein family, without affecting the cooperativity of other members. Lastly, an allosteric modulator, not possessing apparent efficacy, may selectively tune up or down tissue responses in the presence of the endogenous agonist or antagonist, respectively.

Allostery modulation has been identified more and more frequently in the last few years and the number of documented allosteric proteins has been quickly rising. A range of examples illustrating mechanisms of protein allostery are reported here focusing on drugs and related compounds acting as allosteric effectors. The general and widespread features observed in this rapidly growing class of proteins seems to confirm the old forecast by Monod in the early 60’s that “ Allostery is the second secret of life”.

Prof. Dr. Paolo Ascenzi
Prof. Dr. Massimo Coletta
Guest Editors

Published Papers (7 papers)

View options order results:
result details:
Displaying articles 1-7
Export citation of selected articles as:

Research

Jump to: Review

Open AccessArticle Multiple Routes to Oestrogen Antagonism
Pharmaceuticals 2010, 3(11), 3417-3434; doi:10.3390/ph3113417
Received: 26 September 2010 / Revised: 19 October 2010 / Accepted: 25 October 2010 / Published: 29 October 2010
Cited by 1 | PDF Full-text (451 KB) | HTML Full-text | XML Full-text
Abstract
Several lines of evidence attest to the existence of alternative ligand binding sites on the oestrogen receptor (ER), including non-competitive inhibition by trilostane or tamoxifen. It is possible that the inhibitory action of conventional oestrogen agonists at high concentrations may indicate that they
[...] Read more.
Several lines of evidence attest to the existence of alternative ligand binding sites on the oestrogen receptor (ER), including non-competitive inhibition by trilostane or tamoxifen. It is possible that the inhibitory action of conventional oestrogen agonists at high concentrations may indicate that they too interact at alternative ER sites, albeit at low affinity. To test this possibility an oestrogen reporter assay was used to compare the activity of different oestrogens and antagonists in breast cancer and prostate cell lines. All four cell lines tested contained different amounts of oestrogen receptor α (ERα), ERβ, progesterone receptor and coregulator mRNA. Though differences were observed in response to stimulation and inhibition, these correlated only with the presence or absence of ERα, and not with the other components. Thus stimulation of the reporter by oestradiol and oestrone was biphasic in the breast cancer cells, while prostate cells were unable to respond. Only T47D cells were stimulated by oestriol or diethylstilboestrol, however reporter activity of all the cell lines was repressed by 10mM diethylstilboestrol. Reporter activity of MCF-7 cells was inhibited by tamoxifen, raloxifene and ICI 182,780, but stimulated by trilostane, yet all these antioestrogens inhibited agonist-stimulated activity. Trilostane also inhibited the agonism seen in cells co-treated with E2 and tamoxifen. It is clear that several of the compounds tested may have either agonist or antagonist effects under different conditions and at different concentrations, acting through ERα alone. Though biphasic dose response curves, or hormesis, have been attributed to various mechanisms, we here provide evidence that alternative ligand binding sites may contribute to this phenomenon. Full article
(This article belongs to the Special Issue Allosteric Modulation)
Open AccessArticle Dual Allosteric Effect in Glycine/NMDA Receptor Antagonism: A Comparative QSAR Approach
Pharmaceuticals 2010, 3(10), 3167-3185; doi:10.3390/ph3103167
Received: 13 August 2010 / Accepted: 25 September 2010 / Published: 11 October 2010
Cited by 3 | PDF Full-text (395 KB) | HTML Full-text | XML Full-text
Abstract
A comparative Hantzsch type QSAR study was conducted using multiple regression analysis on various sets of quinoxalines, quinoxalin-4-ones, quinazoline-2-carboxylates, 4-hydroxyquinolin-2(1H)-ones, 2-carboxytetrahydroquinolines, phenyl-hydroxy-quinolones, nitroquinolones and 4-substituted-3-phenylquinolin-2(1H)-ones as selective glycine/NMDA site antagonists. Ten statistically validated equations were developed, which indicated the
[...] Read more.
A comparative Hantzsch type QSAR study was conducted using multiple regression analysis on various sets of quinoxalines, quinoxalin-4-ones, quinazoline-2-carboxylates, 4-hydroxyquinolin-2(1H)-ones, 2-carboxytetrahydroquinolines, phenyl-hydroxy-quinolones, nitroquinolones and 4-substituted-3-phenylquinolin-2(1H)-ones as selective glycine/NMDA site antagonists. Ten statistically validated equations were developed, which indicated the importance of CMR, Verloop’s sterimol L1 and ClogP parameters in contributing towards biological activity. Interestingly, normal and inverse parabolic relationships were found with CMR in different series, indicating a dual allosteric binding mode in glycine/NMDA antagonism. Equations reveal an optimum CMR of 10 ± 10% is required for good potency of antagonists. Other equations indicate the presence of anionic functionality at 4-position of quinoline/quinolone ring system is not absolutely required for effective binding. The observations are laterally validated and in accordance with previous studies. Full article
(This article belongs to the Special Issue Allosteric Modulation)

Review

Jump to: Research

Open AccessReview Allosteric Modulation of αβδ GABAA Receptors
Pharmaceuticals 2010, 3(11), 3461-3477; doi:10.3390/ph3113461
Received: 13 September 2010 / Revised: 1 November 2010 / Accepted: 2 November 2010 / Published: 3 November 2010
Cited by 6 | PDF Full-text (312 KB) | HTML Full-text | XML Full-text
Abstract
GABAA receptors mediate the majority of the fast inhibition in the mature brain and play an important role in the pathogenesis of many neurological and psychiatric disorders. The αβδ GABAA receptor localizes extra- or perisynaptically and mediates GABAergic tonic inhibition. Compared
[...] Read more.
GABAA receptors mediate the majority of the fast inhibition in the mature brain and play an important role in the pathogenesis of many neurological and psychiatric disorders. The αβδ GABAA receptor localizes extra- or perisynaptically and mediates GABAergic tonic inhibition. Compared with synaptically localized αβγ receptors, αβδ receptors are more sensitive to GABA, display relatively slower desensitization and exhibit lower efficacy to GABA agonism. Interestingly, αβδ receptors can be positively modulated by a variety of structurally different compounds, even at saturating GABA concentrations. This review focuses on allosteric modulation of recombinant αβδ receptor currents and αβδ receptor-mediated tonic currents by anesthetics and ethanol. The possible mechanisms for the positive modulation of αβδ receptors by these compounds will also be discussed. Full article
(This article belongs to the Special Issue Allosteric Modulation)
Open AccessReview Allosteric Modulation of G Protein Coupled Receptors by Cytoplasmic, Transmembrane and Extracellular Ligands
Pharmaceuticals 2010, 3(10), 3324-3342; doi:10.3390/ph3103324
Received: 9 August 2010 / Revised: 17 October 2010 / Accepted: 25 October 2010 / Published: 25 October 2010
Cited by 5 | PDF Full-text (1294 KB) | HTML Full-text | XML Full-text
Abstract
G protein coupled receptors (GPCRs) bind diverse classes of ligands, and depending on the receptor, these may bind in their transmembrane or the extracellular domains, demonstrating the principal ability of GPCRs to bind ligand in either domains. Most recently, it was also observed
[...] Read more.
G protein coupled receptors (GPCRs) bind diverse classes of ligands, and depending on the receptor, these may bind in their transmembrane or the extracellular domains, demonstrating the principal ability of GPCRs to bind ligand in either domains. Most recently, it was also observed that small molecule ligands can bind in the cytoplasmic domain, and modulate binding and response to extracellular or transmembrane ligands. Thus, all three domains in GPCRs are potential sites for allosteric ligands, and whether a ligand is allosteric or orthosteric depends on the receptor. Here, we will review the evidence supporting the presence of putative binding pockets in all three domains of GPCRs and discuss possible pathways of communication between these pockets. Full article
(This article belongs to the Special Issue Allosteric Modulation)
Open AccessReview Allosteric Inhibitors of NMDA Receptor Functions
Pharmaceuticals 2010, 3(10), 3240-3257; doi:10.3390/ph3103240
Received: 10 August 2010 / Revised: 9 October 2010 / Accepted: 12 October 2010 / Published: 14 October 2010
Cited by 4 | PDF Full-text (1442 KB) | HTML Full-text | XML Full-text
Abstract
NMDA receptors are glutamate-activated ion-channels involved in many essential brain functions including learning, memory, cognition, and behavior. Given this broad range of function it is not surprising that the initial attempts to correct NMDA receptor-mediated pathologies with en-mass receptor blockade were derailed by
[...] Read more.
NMDA receptors are glutamate-activated ion-channels involved in many essential brain functions including learning, memory, cognition, and behavior. Given this broad range of function it is not surprising that the initial attempts to correct NMDA receptor-mediated pathologies with en-mass receptor blockade were derailed by unacceptable side effects. Recent successes with milder or more targeted pharmaceuticals and increasing knowledge of how these receptors operate offer new incentives for rational development of effective NMDA receptor-targeted therapies. In this article we review evidence that L-alanine, a glycine-site partial agonist and pregnanolone sulfate, a use-dependent allosteric inhibitor, while attenuating NMDA receptor activity to similar levels elicit remarkably dissimilar functional outcomes. We suggest that detailed understanding of NMDA receptor activation mechanisms and of structural correlates of function will help better match modulator with function and neurological condition and may unleash the yet untapped potential of NMDA receptor pharmaceutics. Full article
(This article belongs to the Special Issue Allosteric Modulation)
Figures

Open AccessReview Allosteric Modulation of Muscarinic Acetylcholine Receptors
Pharmaceuticals 2010, 3(9), 2838-2860; doi:10.3390/ph3092838
Received: 8 July 2010 / Revised: 17 August 2010 / Accepted: 18 August 2010 / Published: 30 August 2010
Cited by 12 | PDF Full-text (325 KB) | HTML Full-text | XML Full-text
Abstract
An allosteric modulator is a ligand that binds to an allosteric site on the receptor and changes receptor conformation to produce increase (positive cooperativity) or decrease (negative cooperativity) in the binding or action of an orthosteric agonist (e.g., acetylcholine). Since the identification of
[...] Read more.
An allosteric modulator is a ligand that binds to an allosteric site on the receptor and changes receptor conformation to produce increase (positive cooperativity) or decrease (negative cooperativity) in the binding or action of an orthosteric agonist (e.g., acetylcholine). Since the identification of gallamine as the first allosteric modulator of muscarinic receptors in 1976, this unique mode of receptor modulation has been intensively studied by many groups. This review summarizes over 30 years of research on the molecular mechanisms of allosteric interactions of drugs with the receptor and for new allosteric modulators of muscarinic receptors with potential therapeutic use. Identification of positive modulators of acetylcholine binding and function that enhance neurotransmission and the discovery of highly selective allosteric modulators are mile-stones on the way to novel therapeutic agents for the treatment of schizophrenia, Alzheimer’s disease and other disorders involving impaired cognitive function. Full article
(This article belongs to the Special Issue Allosteric Modulation)
Open AccessReview Mechanism of Allosteric Modulation of the Cys-loop Receptors
Pharmaceuticals 2010, 3(8), 2592-2609; doi:10.3390/ph3082592
Received: 24 June 2010 / Revised: 30 July 2010 / Accepted: 9 August 2010 / Published: 12 August 2010
Cited by 5 | PDF Full-text (522 KB) | HTML Full-text | XML Full-text
Abstract
The cys-loop receptor family is a major family of neurotransmitter-operated ion channels. They play important roles in fast synaptic transmission, controlling neuronal excitability, and brain function. These receptors are allosteric proteins, in that binding of a neurotransmitter to its binding site remotely controls
[...] Read more.
The cys-loop receptor family is a major family of neurotransmitter-operated ion channels. They play important roles in fast synaptic transmission, controlling neuronal excitability, and brain function. These receptors are allosteric proteins, in that binding of a neurotransmitter to its binding site remotely controls the channel function. The cys-loop receptors also are subject to allosteric modulation by many pharmaceutical agents and endogenous modulators. By binding to a site of the receptor distinct from the neurotransmitter binding site, allosteric modulators alter the response of the receptors to their agonists. The mechanism of allosteric modulation is traditionally believed to be that allosteric modulators directly change the binding affinity of receptors for their agonists. More recent studies support the notion that these allosteric modulators are very weak agonists or antagonists by themselves. They directly alter channel gating, and thus change the distribution of the receptor across multiple different affinity states, indirectly influencing receptors’ sensitivity to agonists. There are two major locations of allosteric modulator binding sites. One is in subunit interfaces of the amino-terminal domain. The other is in the transmembrane domain close to the channel gating machinery. In this review, we also give some examples of well characterized allosteric binding pockets. Full article
(This article belongs to the Special Issue Allosteric Modulation)
Figures

Journal Contact

MDPI AG
Pharmaceuticals Editorial Office
St. Alban-Anlage 66, 4052 Basel, Switzerland
pharmaceuticals@mdpi.com
Tel. +41 61 683 77 34
Fax: +41 61 302 89 18
Editorial Board
Contact Details Submit to Pharmaceuticals
Back to Top