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Next-Generation Techniques for Determination of Protein-Protein Interactions: Beyond the Crystal Structure

  • Update on Technological Innovations for Cancer Detection and Treatment (T Dickherber, Section Editor)
  • Published:
Current Pathobiology Reports

Abstract

Purpose of Review

We discuss recent advancements in structural biology methods for investigating sites of protein-protein interactions. We will inform readers outside the field of structural biology about techniques beyond crystallography and how these different technologies can be utilized for drug development.

Recent Findings

Advancements in cryo-electron microscopy (cryoEM) and micro-electron diffraction (microED) may change how we view atomic resolution structural biology, such that well-ordered macrocrystals of protein complexes are not required for interface identification. However, some drug discovery applications, such as lead peptide compound generation, may not require atomic resolution; mass spectrometry techniques can provide an expedited path to a generation of lead compounds. New cross-linking compounds, more user-friendly data analysis, and novel protocols such as protein painting can advance drug discovery programs, even in the absence of atomic resolution structural data. Finally, artificial intelligence and machine learning methods, while never truly replacing experimental methods, may provide rational ways to stratify potential druggable regions identified with mass spectrometry into higher and lower priority candidates.

Summary

Electron diffraction of nanocrystals combines the benefits of both x-ray diffraction and cryoEM, and may prove to be the next generation of atomic resolution protein-protein interface identification. However, in situations such as peptide drug discovery, mass spectrometry techniques supported by advancements in computational methods will likely prove sufficient to support drug discovery efforts. In addition, these methods can be significantly faster than any crystallographic or cryoEM methods for the identification of interacting regions.

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Acknowledgments

We gratefully acknowledge the NCI’s Innovative Molecular Analysis Technology (IMAT) program, under which protein painting was developed.

Funding

The work of RC, AL, LL, and AH is supported in part by NIH through NIH NIAMS RO1AR068436, NIH NCI R33CA206937, and the Center for Innovative Technology Award MF18-007-LS.

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  1. Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA

    Rachel Carter, Alessandra Luchini, Lance Liotta & Amanda Haymond

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  1. Rachel Carter
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Carter, R., Luchini, A., Liotta, L. et al. Next-Generation Techniques for Determination of Protein-Protein Interactions: Beyond the Crystal Structure. Curr Pathobiol Rep 7, 61–71 (2019). https://doi.org/10.1007/s40139-019-00198-2

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