Twenty years of gas phase structural biology

Over the past two decades, mass spectrometry (MS) of protein complexes from their native state has made inroads into structural biology. To coincide with the 20(th) anniversary of Structure, and given that it is now approximately 20 years since the first mass spectra of noncovalent protein complexes were reported, it is timely to consider progress of MS as a structural biology tool. Early reports focused on soluble complexes, contributing to ligand binding studies, subunit interaction maps, and topological models. Recent discoveries have enabled delivery of membrane complexes, encapsulated in detergent micelles, prompting new opportunities. By maintaining interactions between membrane and cytoplasmic subunits in the gas phase, it is now possible to investigate the effects of lipids, nucleotides, and drugs on intact membrane assemblies. These investigations reveal allosteric and synergistic effects of small molecule binding and expose the consequences of posttranslational modifications. In this review, we consider recent progress in the study of protein complexes, focusing particularly on complexes extracted from membranes, and outline future prospects for gas phase structural biology.