- Julia María Contreras
- Rubén Julio Martínez
- Hipólito Nicolás Cuesta
- Ana Martín
- Moustafa Ahmed Mohamed Shehata
Rational and precise targeting of oncogene-driven signalling is a crucial but still pending challenge in current 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 posttranslational modifications and allosteric inputs, and how they assemble into macromolecular protein complexes to transmit signals inside the cell. We place 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 more potent and specific protein kinase inhibitors, leading eventually to more effective drugs for the treatment of cancer patients.
We apply an integrated and multidisciplinary approach combining molecular biology for the generation of suitable constructs, protein biochemistry and biophysics for protein purification, quality assessment and functional evaluation, mass spectrometry (MS) for the quantification of posttranslational modifications, X-ray crystallography, and in vivo validation using Drosophila models. Furthermore, we use structure-guided drug discovery and MD simulation approaches to exploit structural and functional vulnerabilities for the design, development, and optimisation of optimal protein kinase inhibitors.
- (2019). Hybrid Histidine Kinase Activation by Cyclic di-GMP-mediated Domain Liberation.. Proc Natl Acad Sci USA (in press). Publication in other institutions.
- (2018). Structure and function of RET in multiple endocrine neoplasia type 2. Endocr-Relat Cancer 25, T79-T90. CNIO Publication.
- (2018). Novel targeted Therapeutics for MEN2. Endocr-Relat Cancer 25, T53-T68. CNIO Publication.
- (2016). RET Functions as a Dual-Specificity Kinase that Requires Allosteric Inputs from Juxtamembrane Elements.. Cell Reports 17, 3319-3332. Publication in other institutions.
- (2016). Cyclic di-GMP mediates a histidine kinase/phosphatase switch by noncovalent domain cross-linking.. Sci Adv 2, e1600823. Publication in other institutions.