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dc.contributor.authorEdman, Karl
dc.contributor.authorHosseini, Ali
dc.contributor.authorBjursell, Magnus K.
dc.contributor.authorAagaard, Anna
dc.contributor.authorWissler, Lisa
dc.contributor.authorGunnarsson, Anders
dc.contributor.authorKaminski, Tim
dc.contributor.authorKöhler, Christian
dc.contributor.authorBäckström, Stefan
dc.contributor.authorJensen, Tina J.
dc.contributor.authorCavallin, Anders
dc.contributor.authorKarlsson, Ulla
dc.contributor.authorNilsson, Ewa
dc.contributor.authorLecina, Daniel
dc.contributor.authorTakahashi, Ryoji
dc.contributor.authorGrebner, Christoph
dc.contributor.authorGeschwindner, Stefan
dc.contributor.authorLepistö, Matti
dc.contributor.authorHogner, Anders C.
dc.contributor.authorGuallar, Víctor
dc.contributor.otherBarcelona Supercomputing Center
dc.date.accessioned2016-03-11T10:24:14Z
dc.date.available2016-12-01T01:30:31Z
dc.date.issued2015-12-01
dc.identifier.citationEdman, Karl [et al.]. Ligand binding mechanism in steroid receptors; from conserved plasticity to differential evolutionary constraints. "Structure", 01 Desembre 2015, vol. 23, núm. 12, p. 2280-2290.
dc.identifier.issn0969-2126
dc.identifier.urihttp://hdl.handle.net/2117/84197
dc.description.abstractSteroid receptor drugs have been available for more than half a century, but details 24 of the ligand binding mechanism has remained elusive. We solved X-ray structures of 25 the glucocorticoid and mineralocorticoid receptors to identify a conserved plasticity at 26 helix 6-7 region that extend the ligand binding pocket towards the receptor surface. 27 Since none of the endogenous ligands exploit this region, we hypothesized that it 28 constitutes an integral part of the binding event. Extensive all atom unbiased ligand 29 exit and entrance simulations corroborate a ligand binding pathway that gives the 30 observed structural plasticity a key functional role. Kinetic measurements reveal that 31 the receptor residence time correlate with structural rearrangements observed in both 32 structures and simulations. Ultimately, our findings reveal why nature has conserved 33 the capacity to open up this region and highlight how differences in the details of the 34 ligand entry process result in differential evolutionary constraints across the steroid 35 receptors.
dc.description.sponsorshipThis study was supported by The European Research Council (2009-Adg25027-535 PELE) to V.G and by the SEV-2011-00067 grant of the Severo Ochoa Program. We 536 would like to acknowledge our AstraZeneca colleagues J. Hartleib, R.Unwin and 537 R.Knöll for helpful discussions. We also thank N. Blomberg (ELIXIR) and R. Neutze 538 (University of Gothenburg) for careful reading of the manuscript.
dc.format.extent10 p.
dc.language.isoeng
dc.publisherElsevier
dc.subjectÀrees temàtiques de la UPC::Enginyeria mecànica::Impacte ambiental
dc.subject.lcshatoms
dc.subject.otherSteroid receptor drugs
dc.subject.otherAmino acid sequence
dc.titleLigand binding mechanism in steroid receptors; from conserved plasticity to differential evolutionary constraints
dc.typeArticle
dc.subject.lemacÀtoms
dc.identifier.doi10.1016/j.str.2015.09.012
dc.description.peerreviewedPeer Reviewed
dc.relation.publisherversionhttp://www.cell.com/structure/fulltext/S0969-2126(15)00404-9
dc.rights.accessOpen Access
dc.description.versionPostprint (author's final draft)
dc.relation.projectidinfo:eu-repo/grantAgreement/EC/FP7/250277/EU/P.E.L.E (Protein Energy Landscape Exploration): a la carte drug design tools/PELE
dc.relation.projectidinfo:eu-repo/grantAgreement/SEV-2011-00067
local.citation.publicationNameStructure
local.citation.volume23
local.citation.number12
local.citation.startingPage2280
local.citation.endingPage2290


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