Chen I

Coyle SM

Crothers DM

De Juan D

Harms MJ

Jaffe EK

Kim S

Larion M

Liggett SB

Motlagh HN

Nussinov R

Weinkam P

Wootten D

Clinical and Translational Medicine

Peixin Huang

Elena López Villar

Crossref

Huang and López Villar Clinical and Translational Medicine 2014, 3:18http://www.clintransmed.com/content/3/1/18COMMENTARY Open AccessPossible mechanism and clinical potentials ofallosteryPeixin Huang1* and Elena López Villar2AbstractAllostery is involved in the dynamic regulation of biological functions in proteins. Advances in allostery researchhave recently drawn great interest and brought allostery closer to the clinic. The present commentary describes themechanism by which allostery may involve in from a cell-wide view and its contribution to the discovery of newtherapeutics to diseases.Keywords: Allostery; DNA; Disease; DrugBackgroundAllostery is a universal phenomenon whereby an effectormolecule combining with a (allosteric) site on the proteinsurface leads to a functional change through alteration ofshape and/or dynamics, to regulate protein activity. Ef-fector perturbations can result from a wide range of bio-logical and physical phenomena, including the binding ofa small effector molecule, post-translational modifications,protein binding, temperature changes, and pH changes.Allostery takes place in all dynamic proteins, single chains,and in RNA and DNA polymers.Main textNumerous studies demonstrated the importance of theallostery on the protein level, such as MAP kinase, G-protein-coupled receptor (GRCR) kinase, glucokinase(GCK), Hemoglobin S etc. to involve in gene regulation[1-4]. Evolution has exploited allostery as a crucial proteinproperty and optimized it for function [5,6]. Recently, aseries of studies reported that the allostery also occurredthrough RNA and DNA, in addition to the protein level.Three DNA-protein pairs (Cy3B-labled DNA binding do-main of glucocorticoid receptor (GRDBD) together withBamHI, Lac repressor (LacR) with EcoRV, or LacR withT7 RNA polymerase) were used to validate and quantita-tively characterize the allostery [7-9]. The deformation ofthe double-helical structure was suggested to be the origin* Correspondence: huang.peixin@zs-hospital.sh.cn1Liver Cancer Institute, Pulmonary Department, Fudan University ZhongshanHospital, Shanghai 200032, ChinaFull list of author information is available at the end of the article© 2014 Huang and López Villar; licensee SpringCommons Attribution License (http://creativecoreproduction in any medium, provided the origof DNA allostery. However, the altered distance of half ahelical turn might affect the evolution with fine-tuningcapability of adjusting relative kinetics in regulatory net-works. Allostery through DNA was found to be more rela-tive to the placement of regulatory elements such as thetransmission of structural influences and switches be-tween canonical structural models.DiscussionHowever, people gradually found that the fundamentalimportance of allostery is not in the protein or DNA levelbut, rather, on the cells. From a cell-wide view, allostericchanges can function through a number of pathways whichare communicated within, across and between cells.Allostery propagates via molecular cooperativenessand recognition specificity, and affects consecutivecomponents in cellular pathways. The main stand-points to descript how allostery works are thermody-namics, free energy landscape of population shift, andstructure [10,11]. Allosteric proteins could activate theconformation of different kinase families and mayshare a similar structure and the same mechanism. Up-stream allosteric sites could switch from inactive αC-helix-out state (OFF) to the active αC-helix-in conform-ation (ON) [12]. It promotes the inter-connection withseveral signaling pathways and the formation of allo-stery network linkage. When mutations cause a highpopulation of ON or OFF states, or lead to an irreversiblechange in active site shape and dynamics, the allostericdiseases occur [13]. Based on such principle, allostericdrugs targeted at those structures and pathways willer. This is an Open Access article distributed under the terms of the Creativemmons.org/licenses/by/4.0), which permits unrestricted use, distribution, andinal work is properly credited.Protein /DNAAllosteryBiological functionsEvolutionDeleteriousHemoglobin S/ GPRC KinaseMAP kinase/DrugsSignaling pathways networkdiseaseDrugsEffectorsMAP KinaseGPRC KinasePI3K/AKT1MEK1PDK1 and etc.targettargetFigure 1 Allostery in gene regulation. Effector molecules bind at the protein's allosteric sites, leading to the changes of protein activity.Allostery of protein or DNA then play their respective biological roles through similar signaling pathways in evolution or deleterious physiologicalprocess to cause diseases. Targeting signaling pathways or allosteric sites may provide promising therapeutic choices for new drugs.Huang and López Villar Clinical and Translational Medicine 2014, 3:18 Page 2 of 3http://www.clintransmed.com/content/3/1/18provide the possibility of new therapeutics. These path-ways may include PI3K/Akt1, MEK1, PDK1 and otherprotein kinases family pathways [14]. For example, anew model for allosteric regulation of phenylalaninehydroxylase has been studied and ACT interface maybe the potential molecule target for therapy [15]. Allo-steric ligands bind to protein receptors such as GPCRsalso provide the ways for allosteric drugs screening andleading to potential therapeutic benefit [16].ConclusionA collection of recently published papers suggest that allo-stery of protein or DNA play the respective biologicalroles in evolution or physiological process. The perturb-ation, such as mutation, phosphorylation and reactionwith small molecules at any site in the protein or DNAstructure, leads to a shift in the distribution of the con-formational states. The irreversible changes in the struc-ture or the abnormality of switch in allostery are thecause of diseases. Those allosteries may share similarsignaling pathways and form network regulation in dis-ease development and may provide promising thera-peutic choices for new drugs (Figure 1). Therefore,allostery plays a key role in gene regulation and can bea new alternative to develop new therapies for diseases.Effects of allosteric changes in the pathway should gainmore special attentions from a comprehensive and dy-namic network perspective.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsPH, ELV collaborated in order to publish this article and to carry out futureresearch studies. Both authors read and approved the final manuscript.AcknowledgementsThe work was supported by Shanghai Health Bureau Research Fund (No.2010/50), The National Nature Science Foundation of China (91230204,81270099, 81320108001, 81270131), The Shanghai Committee of Science andTechnology (12JC1402200, 12431900207, 11410708600), and Spanish healthsystem “Dr E. Lopez Villar, BOE 2012”, ISCIII (PI13/02475FIS “BOE 2013”).Author details1Liver Cancer Institute, Pulmonary Department, Fudan University ZhongshanHospital, Shanghai 200032, China. 2Department of Oncohematology ofChildren, Hospital Universitario Niño Jesús, Avda. Menéndez Pelayo, NO 65,28009 Madrid, Spain.Received: 20 February 2014 Accepted: 16 June 2014Published: 3 July 2014References1. Coyle SM, Flores J, Lim WA: Exploitation of latent allostery enables theevolution of new modes of MAP Kinase regulation. Cell 2013, 154(4):875–887.2. Larion M, Salinas RK, Bruschweiler Li L, Miller BG, Bruschweiler R: Order–disordertransitions govern kinetic cooperativity and allostery of monomeric humanglucokinase. PLoS Biol 2012, 10(12):1001452. 2012-01-20.3. Liggett SB: Phosphorylation barcoding as a mechanism of directingGPCR signaling. Sci Signal 2011, 4(185):e36. 2011-08-09.4. Weinkam P, Sali A: Mapping polymerization and allostery of hemoglobin susing point mutations. J Phys Chem B 2013, 117(42):13058–68. 2013-09-09.5. Harms MJ, Thornton JW: Evolutionary biochemistry: revealing thehistorical and physical causes of protein properties. Nat Rev Genet 2013,14(8):559–571. 2013-08-01.Huang and López Villar Clinical and Translational Medicine 2014, 3:18 Page 3 of 3http://www.clintransmed.com/content/3/1/186. De Juan D, Pazos F, Valencia A: Emerging methods in protein co-evolution.Nat Rev Genet 2013, 14(4):249–261. 2013-04-01.7. Kim S, Brostromer E, Xing D, Jin J, Chong S, Ge H, Wang S, Gu C, Yang L,Gao YQ, Su XD, Sun Y, Xie XS: Probing allostery through DNA. Science2013, 339(6121):816–819. 2013-02-15.8. Chen I: Allostery through DNA. Nat Struct Mol Biol 2013, 20(4):410. 2013-04-01.9. Crothers DM: Biophysics. Fine tuning gene regulation. Science 2013,339(6121):766–767. 2013-02-15.10. Tsai C, Nussinov R: A unified view of “How Allostery Works”. PLoS ComputBiol 2014, 10(2):e1003394. 2014-02-06.11. Motlagh HN, Wrabl JO, Li J, Hilser VJ: The ensemble nature of allostery.Nature 2014, 508(7496):331–339. 2014-04-16.12. Huse M, Kuriyan J: The conformational plasticity of protein kinases.Cell 2002, 109(3):275–282. 2002-05-03.13. Nussinov R, Tsai CJ: Allostery in disease and in drug discovery. Cell 2013,153(2):293–305. 2013-04-11.14. Lu S, Li S, Zhang J: Harnessing allostery: a novel approach to drugdiscovery. Med Res Rev 2014. doi:10.1002/med.21317.[Epub ahead of print].15. Jaffe EK, Stith L, Lawrence SH, Andrake M, Dunbrack RJ: A new model forallosteric regulation of phenylalanine hydroxylase: implications for diseaseand therapeutics. Arch Biochem Biophys 2013, 530(2):73–82. 2013-02-15.16. Wootten D, Christopoulos A, Sexton PM: Emerging paradigms in GPCRallostery: implications for drug discovery. Nat Rev Drug Discov 2013,12(8):630–644. 2013-08-02.doi:10.1186/2001-1326-3-18Cite this article as: Huang and López Villar: Possible mechanism andclinical potentials of allostery. 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Possible mechanism and clinical potentials of allostery

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Possible mechanism and clinical potentials of allostery

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