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WeightNameValue
1000 Titel
  • Molecular sampling of the allosteric binding pocket of the TSH receptor provides discriminative pharmacophores for antagonist and agonists
1000 Autor/in
  1. Hoyer, Inna |
  2. Haas, Ann-Karin |
  3. Kreuchwig, Annika |
  4. Schülein, Ralf |
  5. Krause, Gerd |
1000 Erscheinungsjahr 2013
1000 LeibnizOpen
1000 Art der Datei
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2013-02-01
1000 Erschienen in
1000 Quellenangabe
  • 41(1): 213-217
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2011
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1042/BST20120319 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561627/ |
1000 Ergänzendes Material
  • http://www.biochemsoctrans.org/content/41/1/213.figures-only |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • The TSHR (thyrotropin receptor) is activated endogenously by the large hormone thyrotropin and activated pathologically by auto-antibodies. Both activate and bind at the extracellular domain. Recently, SMLs (small-molecule ligands) have been identified, which bind in an allosteric binding pocket within the transmembrane domain. Modelling driven site-directed mutagenesis of amino acids lining this pocket led to the delineation of activation and inactivation sensitive residues. Modified residues showing CAMs (constitutively activating mutations) indicate signalling-sensitive positions and mark potential trigger points for agonists. Silencing mutations lead to an impairment of basal activity and mark contact points for antagonists. Mapping these residues on to a structural model of TSHR indicates locations where an SML may switch the receptor to an inactive or active conformation. In the present article, we report the effects of SMLs on these signalling-sensitive amino acids at the TSHR. Surprisingly, the antagonistic effect of SML compound 52 was reversed to an agonistic effect, when tested at the CAM Y667A. Switching agonism to antagonism and the reverse by changing either SMLs or residues covering the binding pocket provides detailed knowledge about discriminative pharmacophores. It prepares the basis for rational optimization of new high-affinity antagonists to interfere with the pathogenic activation of the TSHR.
1000 Sacherschließung
lokal constitutively activating mutation
lokal thyrotropin receptor
lokal compound 52
lokal G-coupled-protein receptor
lokal small molecular ligands
1000 Fachgruppe
  1. Biologie |
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/creator/SG95ZXIsIElubmE=|https://frl.publisso.de/adhoc/creator/SGFhcywgQW5uLUthcmlu|https://frl.publisso.de/adhoc/creator/S3JldWNod2lnLCBBbm5pa2E=|https://frl.publisso.de/adhoc/creator/U2Now7xsZWluLCBSYWxm|https://frl.publisso.de/adhoc/creator/S3JhdXNlLCBHZXJk
1000 Label
1000 Förderer
  1. Deutsche Forschungsgemeinschaft (DFG) |
1000 Fördernummer
  1. KR 1273/4-1
1000 Förderprogramm
  1. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft (DFG) |
    1000 Förderprogramm -
    1000 Fördernummer KR 1273/4-1
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6404622.rdf
1000 Erstellt am 2017-09-25T09:20:04.370+0200
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1000 Zuletzt bearbeitet Thu Jan 30 15:55:05 CET 2020
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1000 Vgl. frl:6404622
1000 Oai Id
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