Interested in how molecular dynamics simulations can improve rational drug discovery, particularly at G protein-coupled receptors (GPCRs), the target of over one-third of current clinical drugs. Specifically, what are the structural and dynamic mechanisms governing positive allosteric modulation, biased signalling, and selectivity between closely related… (More)
Smock for their valuable advice at an early stage in this project. A number of other Abt Associates staff contributed invaluable assistance, including Ozan Jaquette, Chris Hamilton, Daniel Weinberg, and Denise Young. All interpretations in this report are our own and do not necessarily reflect the views of the U.S. Department of Heath and Human Services.
The M2 muscarinic receptor is the prototypic model of allostery in GPCRs, yet the molecular and the supramolecular determinants of such effects are unknown. Monomers and oligomers of the M2 muscarinic receptor therefore have been compared to identify those allosteric properties that are gained in oligomers. Allosteric interactions were monitored by means of… (More)