2. Academic Validation
  3. A new mechanism of allostery in a G protein-coupled receptor dimer

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

  • Nat Chem Biol. 2014 Sep;10(9):745-52. doi: 10.1038/nchembio.1593.
J Robert Lane 1,  Prashant Donthamsetti 2,  Jeremy Shonberg 3,  Christopher J Draper-Joyce 1,  Samuel Dentry 1,  Mayako Michino 4,  Lei Shi 5,  Laura López 1,  Peter J Scammells 3,  Ben Capuano 3,  Patrick M Sexton 1,  Jonathan A Javitch 2,  Arthur Christopoulos 1
Affiliations

Affiliations

  • 1 Drug Discovery Biology, Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University-Parkville Campus, Parkville, Victoria, Australia.
  • 2 1] Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York, USA. [2] Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York, USA. [3] Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, USA.
  • 3 Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University-Parkville Campus, Parkville, Victoria, Australia.
  • 4 United States Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA.
  • 5 1] United States Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA. [2] Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York, USA.
PMID: 25108820 DOI: 10.1038/nchembio.1593
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.

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