Main Research Lines
Tubulin assembly and the mechanisms of action of interfacial antitumor drugs.
Self-assembly of αβ-tubulin dimers into microtubules involves the switching of tubulin monomers from a curved conformation into the straight conformation, which is driven by the assembly contacts and fine-tuned by GTP/GDP. Several known microtubule inhibitors bind to curved tubulin, either at the colchicine site at the association interface between tubulin monomers or at the vinblastine site formed between tubuliin dimers. Recently discovered antitumor drugs with a distinct mechanism bind at a new site at the β-tubulin plus end, impairing the association of a next tubulin dimer at the microtubule end (Pera 2013).
Bacterial, plasmid and phage tubulin homologs.
Bacterial tubulin BtubA/B, the closest structural homolog of eukaryotic tubulin, has more primitive assembly properties and divergent surface loop sequences with intertwining features from α- and β-tubulin, suggesting evolution from a tubulin ancestor. BtubA/B folds without chaperones and assembles into microtubule-related polymers with potential biotechnological uses (Martin-Galiano 2011).
TubZs are divergent tubulin-FtsZ homologs that assemble into double helical filaments constituting the motile fibres of type-III plasmid segregation systems. We have described the structure and assembly of TubZ encoded by the toxin carrying Clostridrium botulinum bateriophage cs-t, identified the TubR adaptor protein for segregation of the prophage and a TubY regulatory protein (Oliva 2012).
Targeting FtsZ assembly with small antibacterial molecules.
FtsZ is the organizer for cell division in most bacteria, where it forms the Z-ring that recruits the other divisomal proteins. FtsZ monomers assemble into protofilaments that associate laterally in different fashions. Several GTP analogues selectively inhibit FtsZ polymerization but support tubulin assembly, revealing exploitable differences between the GTP binding sites of both proteins (Marcelo 2013). We have replaced GTP by synthetic molecules that modulate FtsZ assembly, inhibiting the correct Z-ring formation, bacterial cell division and the growth of several antibiotic-resistant pathogens (Ruiz-Avila 2013).
Cooperative assembly of single-stranded FtsZ filaments is thought to involve self-switching of FtsZ monomers from the closed interdomain cleft conformation into an open-cleft conformation with enhanced association interface between monomers. The effective antibacterial compound PC190723 binds into the interdomain cleft, allosterically stabilizing FtsZ filaments. We aim to develop fluorescent probes to find new ligands for this cleft.