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.
The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling / A. Bock, N. Merten, R. Schrage, C. Dallanoce, J. Bätz, J. Klöckner, J. Schmitz, C. Matera, K. Simon, A. Kebig, L. Peters, A. Müller, J. Schrobang-Ley, C. Tränkle, C. Hoffmann, M. De Amici, U. Holzgrabe, E. Kostenis, K. Mohr. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 3:(2012 Sep 03), pp. 1044.1-1044.11. [10.1038/ncomms2028]
The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling
C. Dallanoce;C. Matera;M. De Amici;
2012
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.File | Dimensione | Formato | |
---|---|---|---|
2012NATCOMM.pdf
accesso aperto
Tipologia:
Publisher's version/PDF
Dimensione
795.94 kB
Formato
Adobe PDF
|
795.94 kB | Adobe PDF | Visualizza/Apri |
Pubblicazioni consigliate
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.