The mechanism for ligand activation of the GPCR–G protein complex

Author:

Mafi Amirhossein1ORCID,Kim Soo-Kyung1ORCID,Goddard William A.1ORCID

Affiliation:

1. Materials and Process Simulation Center, California Institute of Technology, Pasadena, CA 91125

Abstract

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.

Funder

DH | National Institute for Health Research

California Institute of Technology

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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