TY - JOUR
T1 - A new mechanism of allostery in a G protein-coupled receptor dimer
AU - Lane, Jonathan Robert David
AU - Donthamsetti, Prashant
AU - Shonberg, Jeremy
AU - Draper-Joyce, Christopher James
AU - Dentry, Samuel
AU - Michino, Mayako
AU - Shi, Lei
AU - Lopez Munoz, Laura
AU - Scammells, Peter John
AU - Capuano, Benvenuto
AU - Sexton, Patrick
AU - Javitch, Jonathan A
AU - Christopoulos, Arthur
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.nature.com/nchembio/journal/v10/n9/pdf/nchembio.1593.pdf
U2 - 10.1038/nchembio.1593
DO - 10.1038/nchembio.1593
M3 - Article
SN - 1552-4450
VL - 10
SP - 745
EP - 752
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 9
ER -