Using hydrogen-deuterium exchange mass spectrometry, researchers have learned more about how G protein-coupled receptors (GPCRs)—proteins that are targets for nearly 40% of marketed drugs—transmit signals (Nature, DOI: 10.1038/nature10488). Roger K. Sunahara of the University of Michigan, Brian K. Kobilka of Stanford University, and colleagues recently reported the first atomic-resolution structure of a GPCR bound to its G protein (C&EN, Aug. 1, page 9). But this static picture provides limited clues about some movements behind G protein activation, including guanosine diphosphate (GDP) release. While performing structural studies, the team joined forces with Virgil L. Woods Jr. of the University of California, San Diego, to study those motions with mass spectrometry. They learned which regions of the G protein become more flexible or more rigid upon binding to a GPCR. “We think the receptor engages the N-terminus of the G protein, tugs on it, and interferes with the region of the G protein that binds the β phosphate of GDP,” triggering release, Sunahara says. He adds that the team’s mass spectrometry conclusions are in agreement with those of electron microscopy work the team recently performed (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.1113645108).