A new mechanism of allostery in a G protein-coupled receptor dimer

Jonathan Robert David Lane, Prashant Donthamsetti, Jeremy Shonberg, Christopher James Draper-Joyce, Samuel Dentry, Mayako Michino, Lei Shi, Laura Lopez Munoz, Peter John Scammells, Benvenuto Capuano, Patrick Sexton, Jonathan A Javitch, Arthur Christopoulos

Research output: Contribution to journalArticleResearchpeer-review

77 Citations (Scopus)

Abstract

SB269652 is to our knowledge the first drug-like allosteric modulator of the dopamine D2 receptor (D2R), but it contains structural features associated with orthosteric D2R antagonists. Using a functional complementation system to control the identity of individual protomers within a dimeric D2R complex, we converted the pharmacology of the interaction between SB269652 and dopamine from allosteric to competitive by impairing ligand binding to one of the protomers, indicating that the allostery requires D2R dimers. Additional experiments identified a bitopic pose for SB269652 extending from the orthosteric site into a secondary pocket at the extracellular end of the transmembrane (TM) domain, involving TM2 and TM7. Engagement of this secondary pocket was a requirement for the allosteric pharmacology of SB269652. This suggests a new mechanism whereby a bitopic ligand binds in an extended pose on one G protein-coupled receptor protomer to allosterically modulate the binding of a ligand to the orthosteric site of a second protomer.
Original languageEnglish
Pages (from-to)745 - 752
Number of pages8
JournalNature Chemical Biology
Volume10
Issue number9
DOIs
Publication statusPublished - 2014

Cite this

Lane, Jonathan Robert David ; Donthamsetti, Prashant ; Shonberg, Jeremy ; Draper-Joyce, Christopher James ; Dentry, Samuel ; Michino, Mayako ; Shi, Lei ; Lopez Munoz, Laura ; Scammells, Peter John ; Capuano, Benvenuto ; Sexton, Patrick ; Javitch, Jonathan A ; Christopoulos, Arthur. / A new mechanism of allostery in a G protein-coupled receptor dimer. In: Nature Chemical Biology. 2014 ; Vol. 10, No. 9. pp. 745 - 752.
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abstract = "SB269652 is to our knowledge the first drug-like allosteric modulator of the dopamine D2 receptor (D2R), but it contains structural features associated with orthosteric D2R antagonists. Using a functional complementation system to control the identity of individual protomers within a dimeric D2R complex, we converted the pharmacology of the interaction between SB269652 and dopamine from allosteric to competitive by impairing ligand binding to one of the protomers, indicating that the allostery requires D2R dimers. Additional experiments identified a bitopic pose for SB269652 extending from the orthosteric site into a secondary pocket at the extracellular end of the transmembrane (TM) domain, involving TM2 and TM7. Engagement of this secondary pocket was a requirement for the allosteric pharmacology of SB269652. This suggests a new mechanism whereby a bitopic ligand binds in an extended pose on one G protein-coupled receptor protomer to allosterically modulate the binding of a ligand to the orthosteric site of a second protomer.",
author = "Lane, {Jonathan Robert David} and Prashant Donthamsetti and Jeremy Shonberg and Draper-Joyce, {Christopher James} and Samuel Dentry and Mayako Michino and Lei Shi and {Lopez Munoz}, Laura and Scammells, {Peter John} and Benvenuto Capuano and Patrick Sexton and Javitch, {Jonathan A} and Arthur Christopoulos",
year = "2014",
doi = "10.1038/nchembio.1593",
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Lane, JRD, Donthamsetti, P, Shonberg, J, Draper-Joyce, CJ, Dentry, S, Michino, M, Shi, L, Lopez Munoz, L, Scammells, PJ, Capuano, B, Sexton, P, Javitch, JA & Christopoulos, A 2014, 'A new mechanism of allostery in a G protein-coupled receptor dimer', Nature Chemical Biology, vol. 10, no. 9, pp. 745 - 752. https://doi.org/10.1038/nchembio.1593

A new mechanism of allostery in a G protein-coupled receptor dimer. / Lane, Jonathan Robert David; Donthamsetti, Prashant; Shonberg, Jeremy; Draper-Joyce, Christopher James; Dentry, Samuel; Michino, Mayako; Shi, Lei; Lopez Munoz, Laura; Scammells, Peter John; Capuano, Benvenuto; Sexton, Patrick; Javitch, Jonathan A; Christopoulos, Arthur.

In: Nature Chemical Biology, Vol. 10, No. 9, 2014, p. 745 - 752.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Javitch, Jonathan A

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