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Signal Transmission Pathways Inside G Protein-Coupled Receptors

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Signal Transmission Pathways Inside G Protein-Coupled Receptors molecules ReviewReview Signaling withinwithin AllostericAllosteric Machines:Machines: SignalSignal TransmissionTransmission PathwaysPathways InsideInside GG Protein-Coupled Protein-CoupledReceptors Receptors 11,, 1,21,2 11 Damian BartuziBartuzi 1,*,* AgnieszkaID , Agnieszka A. Kaczor A. Kaczor and1,2 andDariusz Dariusz Matosiuk Matosiuk 1 11 1 DepartmentDepartment of of Synthesis Synthesis and and Chemical Chemical Technology Technology ofof PharmaceuticalPharmaceutical Substances Substanceswith with Computer Computer Modelling ModellingLab, Medical Lab, University Medical University of Lublin, of 4A Lublin, Chod´zkiStr., 4A Chodźki Lublin Str., PL20093, Lublin Poland; PL20093, Poland;; [email protected]@umlub.pl (A.(A. (A.A.K.);A.K.); [email protected] [email protected] (D.M.)(D.M.) (D.M.) 22 2 SchoolSchool of of Pharmacy, Pharmacy, University University of of Eastern Eastern Finland, Finland, Yliopistonranta Yliopistonranta 1, 1, P.O. P.O. Box Box 1627, 1627, Kuopio FI--70211, FinlandKuopio FI-70211, Finland ** Correspondence:Correspondence: [email protected] [email protected];;; Tel.: Tel.: +48 +48-81-448-7270--81--448--7270 AcademicAcademic Editor:Editor: YungYung HouHou WongWong Received: 13 April 2017 2017;;; Accepted: 10 July 2017 2017;;; Published: date 15 July 2017 Abstract:Abstract: InIn recentrecent years,years, ourour understandingunderstanding of functionfunction of GG protein-coupledprotein--coupled receptors receptors (GPCRs) (GPCRs) has changedchanged from aa picturepicture ofof simple signal relays,relays, transmittingtransmitting only a particularparticular signal to aa particularparticular G proteinprotein heterotrimer,heterotrimer, toto versatileversatile machines,machines, capablecapable ofof variousvarious responsesresponses toto differentdifferent stimulistimuli and being being modulated modulated by by various various factors.factors. factors. Some Some recentrecent recent reportsreports reports provide provide not not only only thethe the data data on onligands/modulatorsligands/modulators ligands/modulators and andresultantresultant resultant signals signals inducedinduced induced by them,them, by them, but also but deeper also deeper insightsinsights insights intointo exact into exactpathways pathways of signal of migration signal migration and mechanisms and mechanisms of signal of transmissiontransmission signal transmission throughthrough receptorreceptor through structur receptore. structure.Combination Combination of thesethese ofcomputational these computational and experimental and experimental data data sheds sheds more more lightlight light on on underlying mechanisms ofof signal signal transmission transmissiontransmission and and signaling signaling bias bias in GPCRs. inin GPCRs. In this InIn review thisthis wereviewreview focus we on focus availablefocus on cluesavailable on allosteric clues on pathwaysallosteric pathways responsible responsibleresponsible for complex forfor signal complex processing signal processing within GPCRs within structures, GPCRs withstructures, particular with emphasisparticular on emphasis linking on compatible linkinglinking compatible in silico- and inin silicoin vitro-- and-derived inin vitro data--derived on the data most on probablethethe most probable allosteric allosteric connections. connections. Keywords: GPCRs; signalin signaling;g; allostery; protein dynamicsdynamics 1. Introduction Introduction Allostery is is oneone ofof thethe mostmost essentialessential propertiesproperties ofof proteins,proteins, makingmaking themthemthem versatileversatile machinesmachines capablecapable ofof complex function. function. The term,term, originating originating inin Greek Greek words words ἄλλοςλλoV (allos—other)(allos(allos—other) andand στερεστερεὀςV (stereos—object)(stereos(stereos—object) was originally used to to describe events occurring in in biological ternary ternary complexes, wherewhere a ligandligand binding binding toto to ‘other‘other ‘other site’ site’ ininin a protein a protein affects affects action action of a of ligandligand a ligand bound bound at ‘orthosteric’‘orthosteric’ at ‘orthosteric’ site, site,i.e.i.e.,, thethe i.e., one the oneresponsibleresponsible responsible forfor main for main protein protein function.function. function. InIn thethe In the present present literatureliterature literature however, however, definition definition of ofallostery allostery isis frequentlyfrequently is frequently broadened broadened toto encompass to encompass all spatially all spatially distant distant effects effects of protein of protein excitation excitation at a atparticular a particular site, even site, evenifif thethe if investigatedinvestigated the investigated complex complex isis composed is composed of only of twotwo only elements. two elements. Deeper Deeperinsightinsight insightintointo principles into principles governing governing functionfunction function of various of various proteins proteins frequentlyfrequently frequently revealsreveals reveals sop sophisticatedhisticated allosteric mechanisms involved, involved, and in in many cases, proteins that that were thought to performperform their function in aa simplesimple and straightforward wayway showshow theirtheir true, true, more complicated face. face. G protein protein-coupled--coupled receptors receptors (GPCRs)(GPCRs) are a good good example example of of such such a a situation. situation. These These receptorsreceptors receptors play play an an essential essential rolerole role inin insignaling signaling inin invertebrates, vertebrates, and and can can be be also also foundfound found inin in invertebrates,invertebrates, invertebrates, fungi,fungi, fungi, plants, plants, or or even protozoa.protozoa. They are responsibleresponsible forfor sensingsensing aa broadbroad varietyvariety ofof impulses,impulses,impulses, includingincludingincluding e.g.,e.g.,, neurotransmitters,neurotransmitters, hormones, ions,ions, proteases,proteases, olfactoryolfactory andand visualvisual stimuli.stimuli. There are ca.ca. 800 800 genes encoding GPCRs inin humanhuman genome, which makes them them the the largest largest family family of humanhuman receptor proteins,proteins,, and one of thethe largestlargest proteinprotein familiesfamiliesfamilies in inin general general [ 1 [[].1] Unsurprisingly,.. Unsurprisingly, this thisthis makes makes them themthem one one of the of the mainthe main drug drug targets—ca. targetstargets— 30%ca. 30% of currently available medicines are targetingtargeting GPCRs [2][2].. All thesethese receptorsreceptors share a common Molecules 20172017,,, 2222,, 1188;1188;; doi:doi:10.3390/molecules2207118810.3390/molecules22071188 www.mdpi.com/journal/moleculeswww.mdpi.com/journal/molecules Molecules 2017, 22, 1188 2 of 24 of currently available medicines are targeting GPCRs [2]. All these receptors share a common fold of seven transmembrane helices connected by three intracellular and three extracellular loops. Most of them share also a number of conserved sequence motifs, and it is suggested that their activation and modulation might be governed by similar mechanisms. GPCRs were once thought to be simple signal relays, receiving extracellular stimuli and transmitting them to a defined species of G proteins in the intracellular space. Notably, even according to this deprecated model, signal transmission within GPCRs could be regarded as an allosteric process, since ligand binding in the extracellular binding pocket was supposed to induce changes at the distant, intracellular site. Recent years, however, brought significant advance in understanding GPCRs function. Today it is known, that they can receive signals and process them, with the signaling outcome depending on the actual structure of a ligand, as well as on presence of additional allosteric factors, like allosteric small molecules, membrane components, ions, or even other GPCRs (in receptor dimers/oligomers). A single GPCR can recognize various ligands, and depending on their nature, it can activate various intracellular signaling cascades, involving different G protein heterotrimers, arrestins or scaffolding proteins. Moreover, it is known, that these pathways can be activated separately by appropriate ligands—this phenomenon is called ‘functional selectivity’. Therefore, it can be concluded that in order to activate different signaling cascades, functionally selective ligands have to activate different intra-protein signal transmission pathways, which in turn suggests that there are more than one way of signal processing in GPCRs. This means that they should rather be considered as complex allosteric machines capable of processing the signal within their structure and returning different responses to different stimuli. In this review, we focus on allosteric pathways responsible for such complex signal processing within GPCRs structures. 1.1. Allosteric Pockets in GPCRs Knowledge of possible allosteric pockets in GPCRs is an important clue. Such pockets are most probably located at the end or along an allosteric pathway, and since many GPCRs share the seven transmembrane (7TM) scaffold as well as numerous conserved sequence motifs, such pathways might be present in many related receptors. In contrast to the orthosteric pockets in receptor structures, allosteric binding sites are often less defined and can be located in various areas. Since native stimuli usually come from the extracellular side, orthosteric pockets are also located at this side of the receptor,
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