FeatureReviewTheLandscapeofAtypicalandEukaryoticProteinKinasesGeorgiK.Kanev,1,2ChrisdeGraaf,1,3IwanJ.P.deEsch,1RobLeurs,1ThomasWu¨rdinger,2BartA.Westerman,2,5,*andAlbertJ.Kooistra1,4,5,*Kinasesareattractiveanticancertargetsduetotheircentralroleinthegrowth,survival,andtherapyresistanceoftumorcells.Thisreviewexploresthetwoprimarykinaseclasses,theeukaryoticproteinkinases(ePKs)andtheatypicalproteinkinases(aPKs),andprovidesastruc-ture-centeredcomparisonoftheirsequences,structures,hydrophobicspines,mutationandSNPhotspots,andinhibitorinteractionpatterns.Despitethelimitedsequencesimilaritybetweenthesetwoclasses,atypicalkinasescommonlysharethearchetypicalkinasefoldbutlackconservedeukaryotickinasemotifsandpossessalteredhydrophobicspines.Furthermore,atypicalkinaseinhibitorsexploreonlyalimitednumberofbindingmodesbothinsideandoutsidetheorthostericbindingsite.Thedistributionofgeneticvariationsinbothclassesshowsmultiplewaystheycaninterferewithkinaseinhibitorbinding.Thismultilayeredreviewprovidesaresearchframeworkbridgingtheeukaryoticandatypicalkinaseclasses.TwoClassesofProteinKinases:AtypicalandEukaryoticKinasesProteinkinasesregulatecellsignalingbycatalyzingthetransferoftheterminalphosphategroupofATPtosubstrateproteins[1].Primarilyduetotheirpivotalroleincancer,proteinkinaseshavebeensubjecttodrugdevelopmenteffortsthatresultedintheapprovalofmorethan50small-moleculeki-naseinhibitors(Box1)bytheUSFDA.The555membersofthehumankinasesuperfamilyhavebeengroupedi,iiintoamainclassof497ePKs(seeGlossary)and,duetolackofsequencesimilarity,58aPKs,whichincludethelipidkinases[2].TheePKclassisfurthersubdividedintoninegroups:AGC,CAMK,CK1,CMGC,Other,RGC,STE,TK,andTKL[3,4].Inthepastthreedecades,extensivestructuralknowl-edgeaboutthissuperfamilyhasbeenacquired.Somewhatsurprisingly,thefirstaPKstructures[5]re-vealedthatseveraloftheseatypicalkinasesalsosharetheprototypicalePKfolddespitetheirlackofsequencesimilarity(Figure1,KeyFigure)[6].Basedontheseinsights,26ofthe58aPKshavebeenfurtherclassifiedasproteink...
