Professor Vlad Pena is a structural biologist focusing on RNA splicing mechanisms and associated gene expression processes. He earned his PhD in structural biology at EMBL in Heidelberg and established his independent laboratory at the Max Planck Institute for Multidisciplinary Sciences in Göttingen. He was later appointed as a Professor in the Division of Structural Biology at the Institute of Cancer Research in London.
Pena's lab employs a multidisciplinary approach to investigate the 3D structure of macromolecular nanomachines. Notable achievements via X-ray crystallography include the first DNA catalyst, the human SF3B complex, and RNA helicase Aquarius. They also revealed the mechanism of splicing modulators (pladienolide, spliceostatin, sudemycin) as competitive antagonists of branch sites. Another finding is that spliceostatin and sudemycin bind spliceosomes by covalent coupling to a zinc finger motif.
Using cryo-EM, Pena's lab unraveled the core of a spliceosome cross-exon A, stalled by spliceostatin. The structure indicates how U2 snRNP recognizes introns via toehold-mediated strand displacement. By capturing the splicing modulator while obstructing the extension of the branch duplex, this structure also explains why the competitive antagonism of modulators is dependent on the intron sequence.
Cryo-EM was crucial in revealing a previously unknown state of the spliceosome, termed BAQR, stalled by inactivating the helicase Aquarius (AQR). The structure of the BAQR was instrumental in describing the catalytic activation in human splicing, which unfolds in two ATP-dependent stages, driven by the helicases PRP2 and Aquarius. Equally remarkable is how the DEAH helicase PRP2 operates on spliceosomes. This molecular motor efficiently translocates a significant 19 nucleotides while concurrently reshaping the spliceosome, thus setting the stage for catalysis.