Christopher J. Draper-Joyce
The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions
Draper-Joyce, Christopher J.; Verma, Ravi Kumar; Michino, Mayako; Shonberg, Jeremy; Kopinathan, Anitha; Herenbrink, Carmen; Scammells, Peter J.; Capuano, Ben; Abramyan, Ara M; Thal, David M.; Javitch, Jonathan A.; Christopoulos, Arthur; Shi, Lei; Lane, J. Robert
Authors
Ravi Kumar Verma
Mayako Michino
Jeremy Shonberg
Anitha Kopinathan
Carmen Herenbrink
Peter J. Scammells
Ben Capuano
Ara M Abramyan
David M. Thal
Jonathan A. Javitch
Arthur Christopoulos
Lei Shi
ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
Associate Professor
Abstract
© 2018 The Author(s). Sodiumions (Na+) allosterically modulate the binding of orthosteric agonists and antagonists to many class A G protein-coupled receptors, including the dopamine D 2 receptor (D 2 R). Experimental and computational evidences have revealed that this effect is mediated by the binding of Na + to a conserved site located beneath the orthosteric binding site (OBS). SB269652 acts as a negative allosteric modulator (NAM) of the D 2 R that adopts an extended bitopic pose, in which the tetrahydroisoquinoline moiety interacts with the OBS and the indole-2-carboxamide moiety occupies a secondary binding pocket (SBP). In this study, we find that the presence of a Na + within the conserved Na + -binding pocket is required for the action of SB269652. Using fragments of SB269652 and novel full-length analogues, we show that Na + is required for the high affinity binding of the tetrahydroisoquinoline moiety within the OBS, and that the interaction of the indole-2-carboxamide moiety with the SBP determines the degree of Na + -sensitivity. Thus, we extend our understanding of the mode of action of this novel class of NAM by showing it acts synergistically with Na + to modulate the binding of orthosteric ligands at the D 2 R, providing opportunities for fine-tuning of modulatory effects in future allosteric drug design efforts.
Citation
Draper-Joyce, C. J., Verma, R. K., Michino, M., Shonberg, J., Kopinathan, A., Herenbrink, C., …Lane, J. R. (2018). The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions. Scientific Reports, 8(1), Article 1208. https://doi.org/10.1038/s41598-018-19642-1
Journal Article Type | Article |
---|---|
Acceptance Date | Dec 19, 2017 |
Online Publication Date | Jan 19, 2018 |
Publication Date | Jan 19, 2018 |
Deposit Date | Apr 22, 2020 |
Publicly Available Date | Jun 8, 2020 |
Journal | Scientific Reports |
Print ISSN | 2045-2322 |
Electronic ISSN | 2045-2322 |
Publisher | Nature Publishing Group |
Peer Reviewed | Peer Reviewed |
Volume | 8 |
Issue | 1 |
Article Number | 1208 |
DOI | https://doi.org/10.1038/s41598-018-19642-1 |
Public URL | http://dx.doi.org/10.1038/s41598-018-19642-1 |
Publisher URL | https://www.nature.com/articles/s41598-018-19642-1 |
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