Research group: Structural Characterization of Macromolecular Assemblies
I am a highly-skilled researcher focused on determining three-dimensional structures of protein, DNA, and RNA macromolecules and their use in structure-based drug design. As a structural biologist, the years of experience have sharpened his analytical, goal-oriented mindset and skills in data presentation and financial applications, including manuscript and grant writing and reviewing.
I have worked with top Lab leaders: ERC grant awardees Bert Poolman (U. of Groningen), Christiane Schaffitzel-Berger (EMBL Grenoble), and Janusz Bujnicki (IIMCB Warsaw); EMBO Member Miquel Coll (IBMB-CSIC/IRB Barcelona), ICREA Research Professor Maria Macias (IRB Barcelona), winning highly competitive grants, including La Caixa PhD Student and Maria-Sklodowska Curie Postdoctoral fellowships, and publishing several high-quality papers in prestigious journals, including PNAS and NAR.
I am naturally curious, eager to learn new things, find creative ways to solve a problem, and finally complete a challenging project. I love science and research and honestly believe that science is the best approach to understanding the world and the key to its progress. In my view, a knowledge-driven society is one of the most critical factors for a sustainable future.
SMAD proteins are central signal transducers of the transforming growth factor-beta (TGF-β) signaling superfamily, which controls plethora of physiological functions in all vertebrates (stem cell pluripotency and differentiation, tissue homeostasis and regeneration, immunity responses, and cancer pathogenesis) Receptor-activated R-SMADs bind Smad4 to form heterotrimeric complexes that interact with DNA and transcription co-activators or co-repressors to fine-tune outcomes of the TGF-β superfamily signaling in multiple cellular context. Furthermore, SMADs influence pri-miRNAs and mRNA processing through interactions with DROSHA, spliceosome, m6A methyltransferase complexes and bind to lncRNAs. Deciphering the structural basis of SMAD-mediated gene expression will help in decoding the contextual framework of the TGF-β cascades and may aid in discovering new therapeutics.
The big picture of the SMAD-cofactor-DNA complexes is still missing, limiting our understanding of how this conserved, universal and complex system works, and in particular how SMAD complexes can interact with so many different promoter sites being associated with the transcription of genes involved in almost all of the cellular processes. The emerging hypothesis in the field is that the selection of binding sites in promoters and formation of functional activator/repressor complexes is ultimately dependent on the identity of the SMAD cofactors binding to SMAD-DNA complexes. In the project, we study how SMAD heterotrimeric proteins interact with their protein cofactors (transcription factors, activators and repressors), and how these interactions modulate the access of the SMAD-cofactor complex to cis regulatory elements. These complexes will provide for the first-time information on heterotrimeric SMAD-binding sites for other proteins, opening the possibilities for drug design and medicinal chemistry studies. Furthermore, different SMAD proteins in the heterotrimeric complex might use different binding sites -or binding modes- to recognize activators and repressors. In these cases, only some of the interactions could be inhibited with small molecules while others remain active. Moreover, if SMAD hotspots could be identified in the complexes, our work would open new possibilities for the rational design of small molecule competitors/inhibitors, to elucidate the complex network of interactions of SMAD-driven signaling. As a result, these molecules could be used to elucidate key steps of TGF- β signaling by perturbing – specifically– only some parts of the signaling cascade. Depending on their specific role, some of these molecules might have a pharmacological application. None of these molecules are currently available in the market for this purpose. Our long-term goal is to determine Cryo-EM structures of these tertiary complexes, identify small molecules that will influence their stability and assembly, and whenever possible provide high resolution X-ray description of the small molecule–protein complexes