Rational and precise targeting of oncogene-driven signalling is a crucial and yet outstanding challenge in cancer research. Understanding the structural and molecular bases of oncogene activation and signalling is key for the design and development of better therapeutics. Our research focuses on the structural and molecular understanding of protein kinase function: how protein kinases are activated and regulated by post-translational modifications and allosteric inputs, and how they assemble into macromolecular protein complexes to transmit signals inside the cell. We put a special emphasis on how these mechanisms are corrupted in cancer due to oncogenic mutations and other oncogenic insults. Crucially, such atomic and molecular information can be translated into the design and development of next generation protein kinase inhibitors for targeted and personalised therapies.
We apply an integrated and multidisciplinary approach combining molecular biology to generate suitable constructs; protein biochemistry and biophysics for protein purification, quality assessment and functional evaluation; mass spectrometry (MS) to identify and quantify post-translational modifications; X-ray crystallography for the 3D-visualisation of proteins; and Drosophila as an in vivo model for data validation. Furthermore, we use structure-guided drug discovery and MD simulation approaches to exploit structural and functional vulnerabilities for drug design and development.
Publicaciones
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Martin-Hurtado A, Contreras Contreras J, Sanchez-Wandelmer J, Zarzuela E, Muñoz IG, Muñoz J, Isasa M and Plaza-Menacho I (2025).The oncogenic CCDC6-RET fusion product is a dual ATP and ADP-dependent kinase that functions via cis-phosphorylation. BioRxiv (in press). Publicación CNIO.
Plaza-Menacho I (2024).Redox takes control. Elife 13, e99765. Publicación CNIO.
Lucena-Agell D, Guillen MJ, Matesanz R, Alvarez-Bernad B, Hortiguela R, Avilés P, Martínez-Díez M, Santamaría-Nuñez G, Contreras J, Plaza-Menacho I, Giménez-Abián J, Oliva MCC, Díaz J (2024).PM534, an optimized target protein interaction strategy through the colchicine site of tubulin. J Med Chem (in press). Publicación CNIO.
Cuesta N, Contreras MJ, Sanchez-Waldermer J, Soriano-Maldonado P, Martin-Hurtado A, Munoz IG, Llimargas M, Munoz J, Plaza- Menacho I (2023).An allosteric switch between the activation loop and a c-terminal palindromic phospho-motif controls c-Src function. Nat Commun 14, 6548. Publicación CNIO. Open Access
Open Access