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Óscar Llorca receives Human Frontiers Science Program award

Madrid, 11 January, 2018

The aim of this project is to achieve a detailed and precise understanding of how chromatin remodelling complexes work

This research combines three cutting-edge techniques based on the design of non-natural amino acids, cryo-electron microscopy and mass spectrometry

This proposal was one of 21 chosen out of 858 submitted initially to this international programme

The Human Frontiers Science Program will provide 1,050,000 dollars in funding over three years to a project led by Óscar Llorca, director of the Structural Biology Programme at the Spanish National Cancer Research Centre (CNIO), which seeks to provide a more accurate understanding of how chromatin remodelling complexes work. The team coordinated by Llorca is working alongside Mark Skehel's Laboratory of Molecular Biology (LMB) in Cambridge and Heinz Neumann's group at the Max Planck Institute in Germany. The project is also grounded in the experience gained by Fabrizio Martino in the study of chromatin. Martino, from the Centre for Biological Research (CIB-CSIC), is also participating in the project.

Some cellular processes are extremely hard to grasp, especially those in which short-lived structures are involved. In such cases, in vitro reconstruction provides limited information, particularly on account of the difficulty reproducing the physiological complexity of the systems.

One clear example is chromatin (the way in which DNA is stored in the cell nucleus) and the hundreds of proteins that regulate and remodel it. These proteins are responsible for "a series of essential modifications to regulate gene expression; a process that is important, for example, in cancer", explains Llorca. “The problem is that we currently know very little about the protein complexes that make these modifications and how they do it".


To overcome the limitations of in vitro techniques and "understand what they are like and how chromatin remodelling complexes work just as they do in the cell", Llorca et al. have designed a new approach that combines three different methodologies: synthetic biology techniques to generate non-natural amino acids as developed by Max Planck's team, cryo-electron microscopy developed in the CNIO, and the LMB's mass spectrometry. 

The idea is to "introduce these non-natural amino acids that have a reactive group and that, when stimulated, join together proximal points in the chromatin and remodelling complexes in order to capture what is happening in the cell at that moment", explained the Spanish researcher. These captured complexes are then subjected to a process of purification and subsequently analysed in two ways. “Using cryo-electron microscopy, we will try to resolve the three-dimensional structure, and the LMB team will be analysing which regions of the chromatin are interacting and which modifications have taken place using mass spectroscopy".

“The ultimate goal is to understand what is happening in the cell with high resolution mechanistic detail thanks to the combination of these three innovative technological processes", concludes Llorca.

The Human Frontiers Science Program is an international initiative that funds cutting-edge projects investigating complex mechanisms of living organisms. Llorca's proposal was one of 21 chosen out of 60 finalists from among 858 projects submitted initially.

Óscar Llorca, Structural Biology Programme director at the CNIO
Óscar Llorca, Structural Biology Programme director at the CNIO./ CNIO

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