Structures are critical for understanding the function of macromolecules and their complexes and to evaluate and develop new drug leads. My group uses X-ray crystallography, cryo-EM, and NMR together with biochemical and biophysical methods, to link the function and structure of macromolecules relevant for cancer.
Our scientific interests revolve around a handful of specific research questions, that concern the interplay between function and structure.
- Autotaxin is a secreted phosphodiesterase that produces the signaling molecule lysophosphatidic acid, LPA. After we determined the structure of Autotaxin and explained its catalytic mechanism, deciphered the role of isoforms and some roles of cell-surface interactions in its activity, we are now focusing on the mechanisms that explain how differences between orthosteric and allosteric inhibitors affect clinical outcome and the role of ATX as a lysolipid carrier.
- Regulation of cell division is ensuring that only one copy of each chromatid goes in each daughter cell during mitosis. We are working on various aspects of this process, including the mechanism of the Bub1 and BubR1 kinases, the role of Spindly in regulating kinetochore maturation, and the Ndc80C complex and Mps1 in regulating microtubule attachemen to the kinetochores.
- Microtubule binding and modifying proteins, is an interested that stemmed from our work on the above interactions with microtubules to regulate mitosis, and the findings of the Thijn Brummelkamp group, that found important microtubule-modifying enzymes.
- JBP1 is the protein that binds the unusual base J in parasites, and is homologous to the TET proteins involved in myeloid leukemia. We are focusing to understand how JBP1 and JBP3 acts to amplify base J in specific regions in the genome of parasites, and specifically in determining their structure through sin gle partciles cryo-EM.
Concurrently our team is involved in many methodology-oriented initiatives, providing scientific developments that enable specific software tools in determining macromolecular structures better and faster.
Over the past decade, my team has been the basis for the development of the PDB-REDO suite. PDB_REDO strives to help crystallographers submit better models to the public PDB archive, but also retro-actively re-refines and re-build the models available, to make sure they all benefit from the most recent developments in the theory and the software in macromolecular crystallography. As part of this effort we make available the pdb-redo.eu site offers tools for optimizing "working models" before they are submitted to the PDB and the PDB-REDO databank, while it communicated validation criteria to the PDBe.org databank.
To determine macromolecular structures, it is important to first make the protein of interest using recombinant DNA technologies. A crucial step is in choosing the right "boundaries" of the protein to make, and many trials are typically required. To that end, in collaboration with the NKI Protein facility we have developed a suite of cloning vectors for ligation independent cloning and the Protein CCD software to design cloning experiments for protein expression in bacteria, insect or mammalian cells.