For the human M2 muscarinic receptor the crystal structures in the active [1] and the inactive [2] conformation are available. Both structures suggest a low tolerance of the receptor protein towards spatial restriction between the allosteric and the orthosteric binding site. Dualsteric compounds consist of covalently linked moieties that address the orthosteric and the allosteric binding site, respectively. Thus, it is possible to constrain receptor flexibility. In a previous study, it was found that dualsteric compounds such as iper-6-naph, in which the orthosteric and allosteric moiety are linked via a hexamethylene chain, show biased signaling (i.e. a preference for Gi over Gs signaling) [3]. Here we present new dualsteric ligands, which due to their molecular properties should further restrict conformational transitions of the receptor. Surprisingly, signaling bias was abolished. These unexpected findings will be discussed in our poster. [1] Haga K. et al.: Nature 2012 [2] Kruse A. et al.: Nature 2013 [3] Bock A. et al.: Nat Chem Biol. 2014
Molecular rigidity in dualsteric agonists affects signaling bias of the muscarinic M2 acetylcholine receptor / F. Krebs, C. Matera, A. Bock, M. Bermudez, G. Wolber, M. De Amici, U. Holzgrabe, K. Mohr. ((Intervento presentato al convegno Symposia on Molecular and Cellular Biology tenutosi a Keystone nel 2016.
Molecular rigidity in dualsteric agonists affects signaling bias of the muscarinic M2 acetylcholine receptor
C. Matera
;M. De Amici
;
2016
Abstract
For the human M2 muscarinic receptor the crystal structures in the active [1] and the inactive [2] conformation are available. Both structures suggest a low tolerance of the receptor protein towards spatial restriction between the allosteric and the orthosteric binding site. Dualsteric compounds consist of covalently linked moieties that address the orthosteric and the allosteric binding site, respectively. Thus, it is possible to constrain receptor flexibility. In a previous study, it was found that dualsteric compounds such as iper-6-naph, in which the orthosteric and allosteric moiety are linked via a hexamethylene chain, show biased signaling (i.e. a preference for Gi over Gs signaling) [3]. Here we present new dualsteric ligands, which due to their molecular properties should further restrict conformational transitions of the receptor. Surprisingly, signaling bias was abolished. These unexpected findings will be discussed in our poster. [1] Haga K. et al.: Nature 2012 [2] Kruse A. et al.: Nature 2013 [3] Bock A. et al.: Nat Chem Biol. 2014
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