title: A new mechanism of allostery in a G protein-coupled receptor dimer.
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.
authors.affiliation: Drug Discovery Biology, Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University-Parkville Campus, Parkville, Victoria, Australia.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Lane
authors.affiliation: 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.
authors.forename: Prashant
authors.initials: P
authors.lastname: Donthamsetti
authors.affiliation: Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University-Parkville Campus, Parkville, Victoria, Australia.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Shonberg
authors.affiliation: Drug Discovery Biology, Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University-Parkville Campus, Parkville, Victoria, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Draper-Joyce
authors.affiliation: Drug Discovery Biology, Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University-Parkville Campus, Parkville, Victoria, Australia.
authors.forename: Samuel
authors.initials: S
authors.lastname: Dentry
authors.affiliation: United States Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Mayako
authors.initials: M
authors.lastname: Michino
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Drug Discovery Biology, Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University-Parkville Campus, Parkville, Victoria, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: López
authors.affiliation: Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University-Parkville Campus, Parkville, Victoria, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
authors.affiliation: Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University-Parkville Campus, Parkville, Victoria, Australia.
authors.forename: Ben
authors.initials: B
authors.lastname: Capuano
authors.affiliation: Drug Discovery Biology, Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University-Parkville Campus, Parkville, Victoria, Australia.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.affiliation: 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.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.affiliation: Drug Discovery Biology, Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University-Parkville Campus, Parkville, Victoria, Australia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D015259:Dopamine Agents / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D011487:Protein Conformation; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015259:Dopamine Agents; D008024:Ligands; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled
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