Advances in integrative structural biology: Towards understanding protein complexes in their cellular context

Abstract

Microorganisms rely on protein interactions to transmit signals, react to stimuli, and grow. One of the best ways to understand these protein interactions is through structural characterization. However, in the past, structural knowledge was limited to stable, high-affinity complexes that could be crystallized. Recent developments in structural biology have revolutionized how protein interactions are characterized. The combination of multiple techniques, known as integrative structural biology, has provided insight into how large protein complexes interact in their native environment. In this mini-review, we describe the past, present, and potential future of integrative structural biology as a tool for characterizing protein interactions in their cellular context.

Keywords: CLEM, correlated light and electron microscopy; Crosslinking mass spectrometry; Cryo-electron microscopy; Cryo-electron tomography; EPR, electron paramagnetic resonance; FRET, Forster resonance energy transfer; ISB, Integrative structural biology; Integrative structural biology; ML, machine learning; MR, molecular replacement; MSAs, multiple sequence alignments; MX, macromolecular crystallography; NMR, nuclear magnetic resonance; PDB, Protein Data Bank; Protein docking; Protein structure prediction; Quinary interactions; SAD, single-wavelength anomalous dispersion; SANS, small angle neutron scattering; SAXS, small angle X-ray scattering; X-ray crystallography; XL-MS, cross-linking mass spectrometry; cryo-EM SPA, cryo-EM single particle analysis; cryo-EM, cryo-electron microscopy; cryo-ET, cryo-electron tomography.