WeightNameValue
1000 Titel
  • Signaling-sensitive amino acids surround the allosteric ligand binding site of the thyrotropin receptor
1000 Autor/in
  1. Kleinau, Gunnar |
  2. Haas, Ann-Karin |
  3. Neumann, Susanne |
  4. Worth, Catherine L. |
  5. Hoyer, Inna |
  6. Furkert, Jens |
  7. Rutz, Claudia |
  8. Gershengorn, Marvin C. |
  9. Schülein, Ralf |
  10. Krause, Gerd |
1000 Erscheinungsjahr 2010
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2010-07
1000 Erschienen in
1000 Quellenangabe
  • 24(7): 2347–2354
1000 FRL-Sammlung
1000 Verlagsversion
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230523/ |
  • http://doi.org/10.1096/fj.09-149146 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • The thyrotropin receptor [thyroid-stimulating hormone receptor (TSHR)], a G-protein-coupled receptor (GPCR), is endogenously activated by thyrotropin, which binds to the extracellular region of the receptor. We previously identified a low-molecular-weight (LMW) agonist of the TSHR and predicted its allosteric binding pocket within the receptor’s transmembrane domain. Because binding of the LMW agonist probably disrupts interactions or leads to formation of new interactions among amino acid residues surrounding the pocket, we tested whether mutation of residues at these positions would lead to constitutive signaling activity. Guided by molecular modeling, we performed site-directed mutagenesis of 24 amino acids in this spatial region, followed by functional characterization of the mutant receptors in terms of expression and signaling, measured as cAMP accumulation. We found that mutations V421I, Y466A, T501A, L587V, M637C, M637W, S641A, Y643F, L645V, and Y667A located in several helices exhibit constitutive activity. Of note is mutation M637W at position 6.48 in transmembrane helix 6, which has a significant effect on the interaction of the receptor with the LMW agonist. In summary, we found that a high proportion of residues in several helices surrounding the allosteric binding site of LMW ligands in the TSHR when mutated lead to constitutively active receptors. Our findings of signaling-sensitive residues in this region of the transmembrane bundle may be of general importance as this domain appears to be evolutionarily retained among GPCRs.—Kleinau, G., Haas, A.-K., Neumann, S., Worth, C. L., Hoyer, I., Furkert, J., Rutz, Gershengorn, M. C., Schülein, R., Krause, G. Signaling-sensitive amino acids surround the allosteric ligand binding site of the thyrotropin receptor.
1000 Sacherschließung
lokal allosteric small molecules
lokal glycoprotein hormone receptors
lokal activation mechanisms
lokal constitutively activating mutations
1000 Fachgruppe
  1. Biologie |
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/creator/S2xlaW5hdSwgR3VubmFy|https://frl.publisso.de/adhoc/creator/SGFhcywgQW5uLUthcmlu|https://frl.publisso.de/adhoc/creator/TmV1bWFubiwgU3VzYW5uZQ==|https://frl.publisso.de/adhoc/creator/V29ydGgsIENhdGhlcmluZSBMLg==|https://frl.publisso.de/adhoc/creator/SG95ZXIsIElubmE=|https://frl.publisso.de/adhoc/creator/RnVya2VydCwgSmVucw==|https://frl.publisso.de/adhoc/creator/UnV0eiwgQ2xhdWRpYQ==|https://frl.publisso.de/adhoc/creator/R2Vyc2hlbmdvcm4sIE1hcnZpbiBDLg==|https://frl.publisso.de/adhoc/creator/U2Now7xsZWluLCBSYWxm|https://frl.publisso.de/adhoc/creator/S3JhdXNlLCBHZXJk
1000 Label
1000 Förderer
  1. Deutsche Forschungsgemeinschaft |
  2. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health |
1000 Fördernummer
  1. KR1273/4-1
  2. -
1000 Förderprogramm
  1. -
  2. Intramural Research Program
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft |
    1000 Förderprogramm -
    1000 Fördernummer KR1273/4-1
  2. 1000 joinedFunding-child
    1000 Förderer National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health |
    1000 Förderprogramm Intramural Research Program
    1000 Fördernummer -
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6402730.rdf
1000 Erstellt am 2017-06-01T13:49:54.399+0200
1000 Erstellt von 25
1000 beschreibt frl:6402730
1000 Bearbeitet von 218
1000 Zuletzt bearbeitet Thu Jan 30 22:55:01 CET 2020
1000 Objekt bearb. Wed Jun 20 12:31:20 CEST 2018
1000 Vgl. frl:6402730
1000 Oai Id
  1. oai:frl.publisso.de:frl:6402730 |
1000 Sichtbarkeit Metadaten public
1000 Sichtbarkeit Daten public
1000 Gegenstand von

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