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 20th 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. [Display omitted] •History of the development of mass spectrometry for membrane protein complexes•Progress from the first mass spectra to the effects of PTMs and lipid binding•Future perspectives including enhanced resolution of mass spectra and ion mobility Over the last two decades, mass spectrometry and its applications to structural biology have come of age. To mark the 20th anniversary of the journal, Marcoux and Robinson trace the pathway to acceptance of this technique from initial forays into protein ligand interactions to the current work on membrane assemblies.