The structural determinants of the bitopic binding mode of a negative allosteric modulator of the dopamine D2 receptor

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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

SB269652 is a negative allosteric modulator of the dopamine D2 receptor (D2R) yet possesses structural similarity to ligands with a competitive mode of interaction. In this study, we aimed to understand the ligand-receptor interactions that confer its allosteric action. We combined site-directed mutagenesis with molecular dynamics simulations using both SB269652 and derivatives from our previous structure activity studies. We identify residues within the conserved orthosteric binding site (OBS) and a secondary binding pocket (SBP) that determine affinity and cooperativity. Our results indicate that interaction with the SBP is a requirement for allosteric pharmacology, but that both competitive and allosteric derivatives of SB269652 can display sensitivity to the mutation of a glutamate residue (E952.65) within the SBP. Our findings provide the molecular basis for the differences in affinity between SB269652 derivatives, and reveal how changes to interactions made by the primary pharmacophore of SB269652 in the orthosteric pocket can confer changes in the interactions made by the secondary pharmacophore in the SBP. Our insights provide a structure-activity framework towards rational optimization of bitopic ligands for D2R with tailored competitive versus allosteric properties.

Original languageEnglish
Pages (from-to)315-328
Number of pages14
JournalBiochemical Pharmacology
Volume148
DOIs
Publication statusPublished - 1 Feb 2018

Keywords

  • Allosteric modulation
  • Bitopic ligands
  • Dopamine receptor
  • G protein-coupled receptor
  • Molecular dynamics simulations
  • Mutagenesis

Cite this

Draper-Joyce, Christopher J. ; Michino, Mayako ; Verma, Ravi Kumar ; Klein Herenbrink, Carmen ; Shonberg, Jeremy ; Kopinathan, Anitha ; Scammells, Peter J. ; Capuano, Ben ; Thal, David M. ; Javitch, Jonathan A. ; Christopoulos, Arthur ; Shi, Lei ; Lane, J. Robert. / The structural determinants of the bitopic binding mode of a negative allosteric modulator of the dopamine D2 receptor. In: Biochemical Pharmacology. 2018 ; Vol. 148. pp. 315-328.
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abstract = "SB269652 is a negative allosteric modulator of the dopamine D2 receptor (D2R) yet possesses structural similarity to ligands with a competitive mode of interaction. In this study, we aimed to understand the ligand-receptor interactions that confer its allosteric action. We combined site-directed mutagenesis with molecular dynamics simulations using both SB269652 and derivatives from our previous structure activity studies. We identify residues within the conserved orthosteric binding site (OBS) and a secondary binding pocket (SBP) that determine affinity and cooperativity. Our results indicate that interaction with the SBP is a requirement for allosteric pharmacology, but that both competitive and allosteric derivatives of SB269652 can display sensitivity to the mutation of a glutamate residue (E952.65) within the SBP. Our findings provide the molecular basis for the differences in affinity between SB269652 derivatives, and reveal how changes to interactions made by the primary pharmacophore of SB269652 in the orthosteric pocket can confer changes in the interactions made by the secondary pharmacophore in the SBP. Our insights provide a structure-activity framework towards rational optimization of bitopic ligands for D2R with tailored competitive versus allosteric properties.",
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author = "Draper-Joyce, {Christopher J.} and Mayako Michino and Verma, {Ravi Kumar} and {Klein Herenbrink}, Carmen and Jeremy Shonberg and Anitha Kopinathan and Scammells, {Peter J.} and Ben Capuano and Thal, {David M.} and Javitch, {Jonathan A.} and Arthur Christopoulos and Lei Shi and Lane, {J. Robert}",
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The structural determinants of the bitopic binding mode of a negative allosteric modulator of the dopamine D2 receptor. / Draper-Joyce, Christopher J.; Michino, Mayako; Verma, Ravi Kumar; Klein Herenbrink, Carmen; Shonberg, Jeremy; Kopinathan, Anitha; Scammells, Peter J.; Capuano, Ben; Thal, David M.; Javitch, Jonathan A.; Christopoulos, Arthur; Shi, Lei; Lane, J. Robert.

In: Biochemical Pharmacology, Vol. 148, 01.02.2018, p. 315-328.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Thal, David M.

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AU - Shi, Lei

AU - Lane, J. Robert

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