The antagonist pGlu-βGlu-pro-NH2 binds to an allosteric site of the thyrotropin-releasing hormone receptor

Daniel L. De La Cruz, Laszlo Prokai, Katalin Prokai-Tatrai

Research output: Contribution to journalArticlepeer-review

Abstract

After we identified pGlu-βGlu-Pro-NH2 as the first functional antagonist of the cholinergic central actions of the thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH2), we became inter-ested in finding the receptor-associated mechanism responsible for this antagonism. By utilizing a human TRH receptor (hTRH-R) homology model, we first refined the active binding site within the transmembrane bundle of this receptor to enhance TRH’s binding affinity. However, this binding site did not accommodate the TRH antagonist. This prompted us to consider a potential allosteric binding site in the extracellular domain (ECD). Searches for ECD binding pockets prompted a remodeling of the extracellular loops and the N-terminus. We found that different trajectories of ECDs produced novel binding cavities that were then systematically probed with TRH, as well as its antagonist. This led us to establish not only a surface-recognition binding site for TRH, but also an allosteric site that exhibited a selective and high-affinity binding for pGlu-βGlu-Pro-NH2. The allosteric binding of this TRH antagonist is more robust than TRH’s binding to its own active site. The findings reported here may shed light on the mechanisms and the multimodal roles by which the ECD of a TRH receptor is involved in agonist and/or antagonist actions.

Original languageEnglish
Article number5397
JournalMolecules
Volume26
Issue number17
DOIs
StatePublished - Sep 2021

Keywords

  • Allosteric binding
  • Docking
  • Extracellular domain
  • G protein-coupled receptor
  • Homology model
  • HTRH-R
  • Surface-recognition binding
  • TRH antagonist
  • TRH receptor

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