The Antagonist pGlu-betaGlu-Pro-NH2 Binds to an Allosteric Site of the Thyrotropin-Releasing Hormone Receptor

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dc.creatorDe La Cruz, Daniel L.
dc.creatorProkai, Laszlo
dc.creatorProkai-Tatrai, Katalin
dc.creator.orcid0000-0001-5595-1346 (Prokai-Tatrai, Katalin)
dc.creator.orcid0000-0002-4559-3458 (Prokai, Laszlo)
dc.date.accessioned2022-11-15T20:25:50Z
dc.date.available2022-11-15T20:25:50Z
dc.date.issued2021-09-05
dc.description.abstractAfter we identified pGlu-betaGlu-Pro-NH2 as the first functional antagonist of the cholinergic central actions of the thyrotropin-releasing hormone (TRH, pGlu-His-Pro-NH2), we became interested 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 directed us to consider a potential allosteric binding site in the extracellular domain (ECD). Searches for ECD binding pockets prompted the 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-betaGlu-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.
dc.description.sponsorshipThis research was funded in part by a UNTHSC Intramural grant (to K.P.-T.) and by The Welch Foundation (endowment BK-0031 to L.P.) and by the National Institute of General Medical Sciences of the National Institutes of Health under award number R25GM125587 (to Harlan P. Jones). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
dc.identifier.citationDe La Cruz, D. L., Prokai, L., & Prokai-Tatrai, K. (2021). The Antagonist pGlu-betaGlu-Pro-NH2 Binds to an Allosteric Site of the Thyrotropin-Releasing Hormone Receptor. Molecules (Basel, Switzerland), 26(17), 5397. https://doi.org/10.3390/molecules26175397
dc.identifier.issn1420-3049
dc.identifier.issue17
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31916
dc.identifier.volume26
dc.publisherMDPI
dc.relation.urihttps://doi.org/10.3390/molecules26175397
dc.rights.holder© 2021 by the authors.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceMolecules
dc.subjectG protein-coupled receptor
dc.subjectTRH antagonist
dc.subjectTRH receptor
dc.subjectallosteric binding
dc.subjectdocking
dc.subjectextracellular domain
dc.subjecthTRH-R
dc.subjecthomology model
dc.subjectsurface-recognition binding
dc.subject.meshAllosteric Site
dc.subject.meshAnimals
dc.subject.meshBinding Sites
dc.subject.meshCatalytic Domain
dc.subject.meshHumans
dc.subject.meshReceptors, Thyrotropin-Releasing Hormone / metabolism
dc.titleThe Antagonist pGlu-betaGlu-Pro-NH2 Binds to an Allosteric Site of the Thyrotropin-Releasing Hormone Receptor
dc.typeArticle
dc.type.materialtext

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