Elucidation of the ATP7B N-Domain Mg2+-ATP Coordination Site and Its Allosteric Regulation 英文参考文献.docVIP

ElucidationoftheATP7BN-DomainMg2+-ATP CoordinationSiteandItsAllostericRegulation ClaudeHercend1,2,CyrilBauvais3,GuillaumeBollot3,NicolasDelacotte3,PhilippeChappuis1 ,France Woimant4,Jean-MarieLaunay1,2,PhilippeManivet1,5,6 * 1APHP,Ho?pitalLariboisie`re,ServicedeBiochimieetdeBiologieMole′culaire,Paris,France,2INSERMU942,BiomarqueursetInsuffisancecardiaque,Ho?pitalLariboisie`re, Paris, France, 3Division of Structural Biology, Bioquanta, Paris, France, 4APHP, Ho?pital Lariboisie`re, Service de Neurologie, Paris, France, 5INSERM U829, SABNP Laboratory,Evry,France,6Universite′ EvryVal-d’Essonne,Evry,France Abstract The diagnostic of orphan genetic disease is often a puzzling task as less attention is paid to the elucidation of the pathophysiology of these rare disorders at the molecular level. We present here a multidisciplinary approach using molecularmodelingtoolsandsurfaceplasmonicresonancetostudythefunctionoftheATP7Bprotein,whichisimpairedin theWilsondisease.Experimentally validatedin silicomodels allow theelucidationin theNucleotidebinding domain(N- 2+ 2+ domain)oftheMg -ATPcoordinationsiteandanswertothecontroversialroleoftheMg ioninthenucleotidebinding process. The analysis ofprotein motionsrevealedasubstantial effect on along flexible loop branched totheN-domain proteincore.WedemonstratedthecapacityofthelooptodisrupttheinteractionbetweenMg -ATPcomplexandtheN- 2+ domainandproposearoleforthisloopintheallostericregulationofthenucleotidebindingprocess. Citation:HercendC,BauvaisC,BollotG,DelacotteN,ChappuisP,etal.(2011)ElucidationoftheATP7BN-DomainMg2+-ATPCoordinationSiteandItsAllosteric Regulation.PLoSONE6(10):e26245.doi:10.1371/journal.pone.0026245 Editor:HendrikW.vanVeen,UniversityofCambridge,UnitedKingdom ReceivedJanuary9,2011;AcceptedSeptember23,2011;PublishedOctober27,2011 Copyright: ? 2011 Hercend et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,dist