TY - JOUR
T1 - The antagonist pGlu-βGlu-pro-NH2 binds to an allosteric site of the thyrotropin-releasing hormone receptor
AU - De La Cruz, Daniel L.
AU - Prokai, Laszlo
AU - Prokai-Tatrai, Katalin
N1 - Funding Information:
Funding: This 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.
Funding Information:
Acknowledgments: D.L.D.L.C. is grateful for the predoctoral fellowship received from the National Institute of General Medical Sciences of the National Institutes of Health under award number R25GM125587 (PI: Harlan P. Jones).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
KW - Allosteric binding
KW - Docking
KW - Extracellular domain
KW - G protein-coupled receptor
KW - HTRH-R
KW - Homology model
KW - Surface-recognition binding
KW - TRH antagonist
KW - TRH receptor
UR - http://www.scopus.com/inward/record.url?scp=85114498535&partnerID=8YFLogxK
U2 - 10.3390/molecules26175397
DO - 10.3390/molecules26175397
M3 - Article
C2 - 34500828
AN - SCOPUS:85114498535
SN - 1420-3049
VL - 26
JO - Molecules
JF - Molecules
IS - 17
M1 - 5397
ER -