Abstract
Integrative structural biology combines data from multiple experimental techniques to generate complete structural models for the biological system of interest. Most commonly cross-linking data sets are employed alongside electron microscopy maps, crystallographic structures, and other data by computational methods that integrate all known information and produce structural models at a level of resolution that is appropriate to the input data. The precision of these modelled solutions is limited by the sparseness of cross-links observed, the length of the cross-linking reagent, the ambiguity arisen from the presence of multiple copies of the same protein, and structural and compositional heterogeneity. In recent years integrative structural biology approaches have been successfully applied to a range of RNA polymerase II complexes. Here we will provide a general background to integrative structural biology, a description of how it should be practically implemented and how it has furthered our understanding of the biology of large transcriptional assemblies. Finally, in the context of recent breakthroughs in microscope and direct electron detector technology, where increasingly EM is capable of resolving structural features directly without the aid of other structural techniques, we will discuss the future role of integrative structural techniques.
Highlights
The goal of structural biology is to derive detailed functional and mechanistic information on a biomolecule from the arrangement of its constituent atoms
Over the last decade the Integrative Structural Determination (ISD) approach has been remarkably successful in modeling the architectures of large, fundamentally important complexes whose structures seemed intractable to single techniques such as those involved in transcription, translation and transit across the nucleus [16–24]
A strong set of phases from multiple isomorphous replacement with anomalous scattering (MIRAS) experiments generated maps that, whilst at a similar resolution to that achieved for the recombinant Head module, revealed features not seen previously such as domain connectivity in the central “Joint” region and large sections of β-sheet within both the “Neck” and the “Fixed Jaw” domains
Summary
159–160 (2019) 4–22 of stochastic sampling for integrative modeling of macromolecular structures, Biophys. [140] Developing a multiplexed quantitative cross-linking mass spectrometry platform for comparative structural analysis of protein complexes - analytical chemistry (ACS Publications), (n.d.). [145] R.D. Cohen, G.J. Pielak, A cell is more than the sum of its (dilute) parts: A brief history of quinary structure, Protein Sci. 26 (2017) 403–413, https://doi.org/10.
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