A Monod-Wyman-Changeux mechanism can explain G protein-coupled receptor (GPCR) allosteric modulation

Meritxell Canals, Jonathan Lane, Adriel Wen, Peter Scammells, Patrick Sexton, Arthur Christopoulos

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89 Citations (Scopus)


The Monod-Wyman-Changeux (MWC) model was initially proposed to describe the allosteric properties of regulatory enzymes, and subsequently extended to receptors. Yet, despite GPCRs representing the largest family of receptors and drug targets, no study has systematically evaluated the MWC mechanism as it applies to GPCR allosteric ligands. We reveal how the recentlydescribed allosteric modulator, benzyl quinolone carboxylic acid (BQCA), behaves according to a strict, two-state, MWC mechanism at the M1 muscarinic acetylcholine receptor (mAChR). Despite having a low affinity for the M1 mAChR, BQCA demonstrated state-dependence, exhibiting high positive cooperativity with orthosteric agonists in a manner that correlated with efficacy, but negative cooperativity with inverse agonists. The activity of BQCA was significantly increased at a constitutively active M1 mAChR, but abolished at an inactive mutant. Interestingly, BQCA possessed intrinsic signaling efficacy, ranging from nearquiescence to full agonism depending on the coupling efficiency of the chosen intracellular pathway. This latter cellular property also determined the difference in magnitude of positive cooperativity between BQCA and the orthosteric agonist, carbachol (CCh), across pathways. The lack of additional, pathwaybiased, allosteric modulation by BQCA was confirmed in genetically engineered yeast strains expressing different chimeras between the endogenous yeast Gpa1 protein and human GI? subunits. These findings define a chemical biological framework that can be applied to the study and classification of allosteric modulators across different GPCR families.
Original languageEnglish
Pages (from-to)650 - 659
Number of pages10
JournalThe Journal of Biological Chemistry
Issue number1
Publication statusPublished - 2012

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