Seminars Archive

New challenges in structural biology: Catching the complexity of dynamic nanomachines

Annalisa Pastore
King’s College, London, UK

Abstract
Structural Biology turned 60 last year if we start counting from the two mythical Nobel prizes awarded to Watson, Crick, and Wilkins, and Perutz and Kendrew in 1962. More than sixty years and several ten thousand structures later, we can now look back and trace the developments of the structural field and consider the new challenges which await us ahead (Berman et al., 2013). We are also in the position to look at the future and reflect on the challenges which await us. A particularly fascinating challenge is to understand the dynamical functioning of entire molecular machines moving beyond the description of static complexes. Machines are typically composed of complex networks of competing interactions which form and disassemble in a time-resolved way. The study of machines recalls other related challenges: can we account in our studies for the complexity of the living cell? Traditionally, Structural Biology has been by election in vitro and relying on the use of highly purified proteins because this is the only way to ensure that what we observe is caused directly by the protein we want to study rather than by impurities or by mediated effects. While this concept cannot be overcome, it has become important to fill the gap between biophysical studies and cellular biology: With this aim, an increasing interest is being paid to studies of molecular crowding in the attempt of designing new ways to approach structural biology in millieux as close as possible to the cellular environment (Cammarata et al., 2022). As a corollary, we also need to develop methodologies that may allow us to look at protein structure directly in cell. Another remarkable aspect that requires increasing attention is how post-translational modifications affect protein structure and modulate interactions. We have for instance seen the importance of modifications for the histone code where a few chemical groups account for the combinatorial complexity which modulates gene expression (Füllgrabe et al., 2014). Finally, for too many years we have focused on proteins and nucleic acids, neglecting other important cellular components such as carbohydrates, lipids and small metabolites. These studies have often been hampered by the complexity of these other systems and the difficulties of producing these molecules in high quantities and purity. It is about time to reconsider these questions and extend our structural studies to include these molecules. In my seminar, I will analyze these important aspects and revise how new emerging techniques may allow us to reach new frontiers of Structural Biology. References Berman, H.M., Coimbatore Narayanan, B., Di Costanzo, L., Dutta, S., Ghosh, S., Hudson, B.P., Lawson, C.L., Peisach, E., Prlić, A., Rose, P.W., Shao, C., Yang, H., Young, J., Zardecki, C. (2009) Trendspotting in the Protein Data Bank. Biochem. J. 417, 621–637. Cammarata, M., Piazza, F., Rivas, G., Schirò, G., Temussi, P.A., Pastore, A. (2023) Revitalizing an important field in biophysics: The new frontiers of molecular crowding. Front Mol Biosci. 10, 1153996. Füllgrabe, J., Heldring, N., Hermanson, O., Joseph, B. (2014) Cracking the survival code: Autophagy-related histone modifications. Autophagy 10.