The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions

Christopher J. Draper-Joyce, Ravi Kumar Verma, Mayako Michino, Jeremy Shonberg, Anitha Kopinathan, Carmen Klein Herenbrink, Peter J. Scammells, Ben Capuano, Ara M. Abramyan, David M. Thal, Jonathan A. Javitch, Arthur Christopoulos, Lei Shi, J. Robert Lane

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Article number1208
Number of pages12
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

Cite this

Draper-Joyce, C. J., Verma, R. K., Michino, M., Shonberg, J., Kopinathan, A., Klein 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), [1208]. https://doi.org/10.1038/s41598-018-19642-1
Draper-Joyce, Christopher J. ; Verma, Ravi Kumar ; Michino, Mayako ; Shonberg, Jeremy ; Kopinathan, Anitha ; Klein Herenbrink, Carmen ; Scammells, Peter J. ; Capuano, Ben ; Abramyan, Ara M. ; Thal, David M. ; Javitch, Jonathan A. ; Christopoulos, Arthur ; Shi, Lei ; Lane, J. Robert. / The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
@article{5cb835ce8c1d45cd96f5b8f8ae62fc59,
title = "The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions",
abstract = "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.",
author = "Draper-Joyce, {Christopher J.} and Verma, {Ravi Kumar} and Mayako Michino and Jeremy Shonberg and Anitha Kopinathan and {Klein Herenbrink}, Carmen and Scammells, {Peter J.} and Ben Capuano and Abramyan, {Ara M.} and Thal, {David M.} and Javitch, {Jonathan A.} and Arthur Christopoulos and Lei Shi and Lane, {J. Robert}",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41598-018-19642-1",
language = "English",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

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; Klein Herenbrink, Carmen; Scammells, Peter J.; Capuano, Ben; Abramyan, Ara M.; Thal, David M.; Javitch, Jonathan A.; Christopoulos, Arthur; Shi, Lei; Lane, J. Robert.

In: Scientific Reports, Vol. 8, No. 1, 1208, 01.12.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions

AU - Draper-Joyce, Christopher J.

AU - Verma, Ravi Kumar

AU - Michino, Mayako

AU - Shonberg, Jeremy

AU - Kopinathan, Anitha

AU - Klein Herenbrink, Carmen

AU - Scammells, Peter J.

AU - Capuano, Ben

AU - Abramyan, Ara M.

AU - Thal, David M.

AU - Javitch, Jonathan A.

AU - Christopoulos, Arthur

AU - Shi, Lei

AU - Lane, J. Robert

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85040808354&partnerID=8YFLogxK

U2 - 10.1038/s41598-018-19642-1

DO - 10.1038/s41598-018-19642-1

M3 - Article

VL - 8

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 1208

ER -