Predicting Inactive Conformations of Protein Kinases Using Active Structures Conformational Selection of Type-II Inhibitors 英文参考文献.docVIP

PredictingInactiveConformationsofProteinKinases UsingActiveStructures:ConformationalSelectionof Type-IIInhibitors MinXu,LuYu,BoWan,LongYu,QiangHuang* StateKeyLaboratoryofGeneticEngineering,SchoolofLifeSciences,FudanUniversity,Shanghai,China Abstract Protein kinases havebeenfoundtopossess twocharacteristic conformations in theiractivation-loops: theactive DFG-in conformation andtheinactive DFG-outconformation. Recently,ithasbeenveryinterestingtodeveloptype-IIinhibitors which target the DFG-out conformation and are more specific than the type-I inhibitors binding to the active DFG-in conformation.However,solvingcrystalstructuresofkinaseswiththeDFG-outconformationremainsachallenge,andthis seriously hampers the application of the structure-based approaches in development of novel type-II inhibitors. To overcome this limitation, here we present a computational approach for predicting the DFG-out inactive conformation usingtheDFG-inactive structures, anddeveloprelatedconformational selection protocolsfor theusesof thepredicted DFG-out models in the binding pose prediction and virtual screening of type-II ligands. With the DFG-out models, we predicted the binding poses for known type-II inhibitors, and the results were found in good agreement with the X-ray crystal structures. We also tested the abilities of the DFG-out models to recognize their specific type-II inhibitors by screeningadatabaseofsmallmolecules.TheAUC(areaundercurve)resultsindicatedthatthepredictedDFG-outmodels wereselectivetowardtheirspecifictype-IIinhibitors.Therefore,thecomputationalapproach andprotocolspresentedin thisstudyareverypromisingforthestructure-baseddesignandscreeningofnoveltype-IIkinaseinhibitors. Citation:XuM,YuL,WanB,YuL,HuangQ(2011)PredictingInactiveConformationsofProteinKinasesUsingActiveStructures:ConformationalSelectionof Type-IIInhibitors.PLoSONE6(7):e22644.doi:10.1371/journal.pone.0022644 Editor:ClaudineMayer,InstitutPasteur,France ReceivedJanuary17,2011;AcceptedJuly3,2011;