LAUSR

Significance We report the detailed atomistic mechanism for how molecules such as morphine, dopamine, or epinephrine binding outside of a cell to a G protein–coupled receptor (GPCR) in the cell membrane cause a G protein (GP) bound at the inside of the cell to break apart and signal the cell to influence appetite, anxiety, memory, cognition, learning, and sleep. Most surprising is that the GP binds first to the GPCR to form a precoupled complex that remains at rest until the drug binds to induce the signaling. Most important, it is the precoupled GPCR-GP structure that provides the basis for the design of therapeutics to maximize activity and selectivity.