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Structural Biology Programme

Director: Óscar Llorca

Programme's research areas and strategic goals

The main goal of the Structural Biology Programme is to use structural information to provide mechanistic understanding at the molecular level of how proteins and macromolecular complexes related to cancer function and, ultimately, to use the new mechanistic insights to help guide future drug design. Collaborations and synergies with other Programmes within the CNIO and the combination of different methodologies are essential to achieve these aims.

2017 has been a year of change for the Programme. The Groups headed by Alfonso Valencia and Santiago Ramón-Maiques have moved to different institutions, and the National Bioinformatics Institute Unit, headed by Salvador Capella, also left the CNIO during 2017. Alfonso Valencia, who led the Programme until February, was also responsible for the Structural Computational Biology Group, contributing, among other aspects, to large-scale genome projects. During Alfonso Valencia's directorship of the Programme several organisational changes took place; in 2016, he managed the selection of candidates for two Junior Group Leader positions, the reorganisation of the Bioinformatics Unit, and the installation of a new cluster, acquired in 2016 but installed during 2017. During their stay at CNIO, Santiago Ramon's Group (Structural Bases of Genome Integrity Group) helped to advance our understanding of genome integrity; they focused mainly on the structure and function of CAD, a key component in the metabolism of pyrimidines.

We are very thankful to all the above mentioned Groups for their dedication and their contribution to the high-level science conducted at the CNIO. We wish them all the best in their new ventures.

Currently, the Programme has several Core Units : Spectroscopy and NMR, Electron Microscopy (EM), Bioinformatics, Crystallography and Protein Engineering, and Biological Text Mining. These Units provide access, maintenance and expertise for technologies in Structural Biology and Bioinformatics. Units are an essential element for the Programme and their activities are vital to facilitate the access to Structural methods for non-experts.

During 2017, three new groups joined the Structural Biology Programme; it now counts three Junior and one Senior Research Groups. The Junior Groups headed by Daniel Lietha and Iván Plaza Menacho, work on structural and mechanistic aspects in cancer cell signalling and protein kinases, with emphasis on the search for new inhibitors. The Junior Group headed by Rafael Fernández-Leiro, and the Senior Group, led by Óscar Llorca, work on genome instability and DNA repair pathways.

Frontier Structural Biology in cancer requires a strong technical component in cryo-electron microscopy (cryo- EM). Incorporating the so-called ‘resolution revolution' in cryo-EM - now capable of observing macromolecules at high resolution - is the Programme's main strategic goal for 2017 and 2018. The Programme has recruited two experts in cryo-EM, Rafael Fernández-Leiro and Óscar Llorca, who are working together with the EM Unit to set up an upgraded facility for highresolution cryo-EM. A new electron microscope with a direct electron detector suitable for high-resolution studies of proteins and complexes is now being acquired. The synergy of cryo-EM with other Structural Biology technologies already in place in the Programme will facilitate the exploitation of the molecular and structural understanding of biological mechanisms for its application in drug design/discovery.

Summary of milestones & major achievements of the Programme during 2017

During 2017, Moreno-Morcillo and colleagues from Santiago Ramón''s Group provided clues to the assembly of the multifunctional protein CAD in the July issue of the journal Structure. Le Coq and colleagues from Daniel Lietha's Group published in the August issue of eLife, new crystal structures of SH2-containing-inositol- 5-phosphatases, proteins that play important roles in regulating the PI3K/Akt pathway in physiology and disease.

Iván Plaza Menacho, Rafael Fernández-Leiro and Óscar Llorca joined the Programme in 2017. We live in exciting times at the Structural Biology Programme; news groups have been recruited and the cryo-electron microscopy equipment is being upgraded. The prospect of using images of single molecules to obtain high-resolution information of complexes will become a reality at CNIO.