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 language | English |
|---|---|
| Article number | 1208 |
| Number of pages | 12 |
| Journal | Scientific Reports |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Dec 2018 |
Cite this
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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 journal › Article › Research › peer-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 -