Protein-Nucleic Acid Complexes

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Protein-nucleic acid complexes consist of proteins bound to  nucleic acids, (DNA or RNA or both). They play roles in many vital processes, such as replication, transcription, translation, and gene expression regulation. The structures of these complexes may provide insights into their biological functions and molecular mechanisms.

While X-ray crystallography has been used to gain structural information about protein-nucleic acid complexes, many complexes fail to crystallize easily, or at all. Advancements in cryo-EM have enabled the determination of structures that were previously unsolvable through crystallography alone. For instance, cryo-EM has successfully solved the structures of human Dicer-type ribonucleases and RNA substrates in a catalytic state, providing information about the mechanism of pre-miRNA processing (PDBID 7XW2, 7XW3). In more recent years, the use of cryo-EM during the COVID-19 pandemic helped to quickly get structures of the SARS-CoV-2 polymerase complex, helping develop drugs aimed at inhibiting virus replication.

Other examples of large protein- nucleic acid complexes solved by cryo-EM include:

  • Transferases
  • Hydrolases
  • Ribosomes
  • Nucleosomes
  • Spliceosomes
Colorful scientific renderings of protein nucleic acids solved by cryo-EM
Cryo-EM structure of human DICER-pre-miRNA in a dicing state at 3.04 Å, 7XW2 (left) and Cryo-EM structure of an apo-form of human DICER at 4.04 Å resolution, 7XW3 (right), from Lee, YY., Lee, H., Kim, H. et al. Structure of the human DICER–pre-miRNA complex in a dicing state. Nature 615, 331–338 (2023).

Analyzing Protein-Nucleic Acid Complexes with Cryo-EM

Structure determination of multicomponent protein-nucleic acid complexes has been hindered by their size, instability and flexibility, which makes them poorly suited to analysis by x-ray crystallography or NMR.  Cryo-EM may overcome most of these limitations, and allow scientists to study protein-nucleic acid complexes  at near-atomic resolution. In addition, Cryo-EM may allow for the capture of dynamic states, providing valuable insights into the mechanisms of nucleic acid binding, interaction and signaling. 

By integrating 3D models and data from other analytical techniques scientists can gain insights into the structural and dynamic changes occurring within protein-nucleic acid complexes at different scales. As cryo-EM and other structural techniques continue to evolve, our understanding of these complexes and their functions will unlock new avenues in biomedical research and pave the way for groundbreaking discoveries in life sciences.

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