Coupling of receptor conformation and ligand orientation determine graded activity

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dc.contributor.authorBruning, J.
dc.contributor.authorParent, A.
dc.contributor.authorGil, G.
dc.contributor.authorZhao, M.
dc.contributor.authorNowak, J.
dc.contributor.authorPace, M.
dc.contributor.authorSmith, C.
dc.contributor.authorAfonine, P.
dc.contributor.authorAdams, P.
dc.contributor.authorKatzenellenbogen, J.
dc.contributor.authorNettles, K.
dc.date.issued2010
dc.description.abstractSmall molecules stabilize specific protein conformations from a larger ensemble, enabling molecular switches that control diverse cellular functions. We show here that the converse also holds true: the conformational state of the estrogen receptor can direct distinct orientations of the bound ligand. 'Gain-of-allostery' mutations that mimic the effects of ligand in driving protein conformation allowed crystallization of the partial agonist ligand WAY-169916 with both the canonical active and inactive conformations of the estrogen receptor. The intermediate transcriptional activity induced by WAY-169916 is associated with the ligand binding differently to the active and inactive conformations of the receptor. Analyses of a series of chemical derivatives demonstrated that altering the ensemble of ligand binding orientations changes signaling output. The coupling of different ligand binding orientations to distinct active and inactive protein conformations defines a new mechanism for titrating allosteric signaling activity.
dc.description.statementofresponsibilityJohn B. Bruning, Alexander A. Parent, German Gil, Min Zhao, Jason Nowak, Margaret C. Pace, Carolyn L. Smith, Pavel V. Afonine, Paul D. Adams, John A. Katzenellenbogen and Kendall W. Nettles
dc.identifier.citationNature Chemical Biology, 2010; 6(11):837-843
dc.identifier.doi10.1038/nchembio.451
dc.identifier.issn1552-4450
dc.identifier.issn1552-4469
dc.identifier.orcidBruning, J. [0000-0002-6919-1824]
dc.identifier.urihttp://hdl.handle.net/2440/75408
dc.language.isoen
dc.publisherNature Publishing Group
dc.rights© 2010 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.
dc.source.urihttps://doi.org/10.1038/nchembio.451
dc.subjectCell Line, Tumor
dc.subjectHumans
dc.subjectBreast Neoplasms
dc.subjectPyrazoles
dc.subjectReceptors, Estrogen
dc.subjectLigands
dc.subjectReverse Transcriptase Polymerase Chain Reaction
dc.subjectSignal Transduction
dc.subjectAllosteric Regulation
dc.subjectBinding Sites
dc.subjectProtein Conformation
dc.subjectDose-Response Relationship, Drug
dc.subjectMutation
dc.subjectTime Factors
dc.titleCoupling of receptor conformation and ligand orientation determine graded activity
dc.typeJournal article
pubs.publication-statusPublished

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