The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling

Nat Commun. 2012;3:1044. doi: 10.1038/ncomms2028.

Abstract

Seven transmembrane helical receptors (7TMRs) modulate cell function via different types of G proteins, often in a ligand-specific manner. Class A 7TMRs harbour allosteric vestibules in the entrance of their ligand-binding cavities, which are in the focus of current drug discovery. However, their biological function remains enigmatic. Here we present a new strategy for probing and manipulating conformational transitions in the allosteric vestibule of label-free 7TMRs using the M(2) acetylcholine receptor as a paradigm. We designed dualsteric agonists as 'tailor-made' chemical probes to trigger graded receptor activation from the acetylcholine-binding site while simultaneously restricting spatial flexibility of the receptor's allosteric vestibule. Our findings reveal for the first time that a 7TMR's allosteric vestibule controls the extent of receptor movement to govern a hierarchical order of G-protein coupling. This is a new concept assigning a biological role to the allosteric vestibule for controlling fidelity of 7TMR signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • GTP-Binding Proteins / metabolism*
  • Humans
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptor, Muscarinic M2 / chemistry*
  • Receptor, Muscarinic M2 / genetics
  • Receptor, Muscarinic M2 / metabolism
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism

Substances

  • CHRM2 protein, human
  • Receptor, Muscarinic M2
  • Receptors, G-Protein-Coupled
  • seven-transmembrane G-protein-coupled receptor
  • GTP-Binding Proteins

Associated data

  • PubChem-Substance/143472893
  • PubChem-Substance/143472894
  • PubChem-Substance/143472895
  • PubChem-Substance/143472896
  • PubChem-Substance/143472897