Research interest: Macromolecular Structures
Macromolecular structures are critical for understanding the
function of proteins and their complexes and to evaluate and
develop new drugs. A key methodology for understanding the
structure of macromolecules is X-ray crystallography. My group is
interested both in analysing macromolecular structures relevant for
cancer, but also in developing the tools needed to decipher these
I have been involved in many methodology oriented initiatives,
providing scientific developments that enable specific software
tools in determining macromolecular structures better and
- The development of the ARP/wARP suite for crystallographic
model building has been the focus of my team for well over a
decade. With more than 5,000 academic of users, close to one
hundred active commercial licenses with companies in the
biotechnology and pharmaceutical area, and well over 5,000
citations in international literature, ARP/wARP is established as a
major tool for routine crystallographic structure determination.
Our interest and major contributions to ARP/wARP have been to
develop algorithms for docking the structure fragments to know
sequences, building the side chain conformations, modeling surface
loops, and developing the control systems and interfaces that make
ARP/wARP easy and powerful to use for every crystallographer,
novice or experienced.
- Over the last few years, my team has been the basis for the
development of the PDB_REDO suite. Capitalizing on our experience
in developing algorithms for model building in ARP/wARP, we
developed new tools that help rebuild and re-refine models that are
already in the PDB or are about to be submitted to the PDB.
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 for optimizing "working models"
before they are submitted to the PDB.
PDB_REDO has started a decade ago in the group of Gert Vriend
at the Radboud University Medical Center at Nijmegen, as a software
pipeline to remediate all PDB entries, by re-refining them with
modern software. Since 2009, the original PDB_REDO developer Robbie
Joosten has joined my team, and capitalising on our experience in
developing algorithms for model building in ARP/wARP. We have since
then developed new tools to rebuild macromolecular models and new
decision and validation algorithms to improve and extend the score
of this pipeline. PDB_REDO strives to help crystallographers submit
better models to the public PDB archive, but also retro-actively
re-refines and re-builds 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 for optimizing "working models"
before they are submitted to the PDB.
- 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.
Our scientific interests revolve around a handful of specific
research questions, that concern the interplay between function and
structure. Most proteins have a specific enzymatic activity that
drives a chemical reaction necessary to fulfill their physiological
function. Many proteins, are made by multiple domains, or interact
with other proteins, to direct their enzymatic activity in space
and time. A common theme in our group is to understand the
spatiotemporal control that interactions with other proteins (and
with small domains within the same protein) exert on the activity
of the 'host' protein, at the level of the molecular structure and
physiological function. We use X-ray crystallography, X-ray
scattering, and a variety of biophysical methods to answer these
- Autotaxin is a secreted phosphodiesterase that produces the
signaling molecule lysophosphatidic acid, LPA. We have determined
the structure of Autotaxin alone and with an in-house developed
inhibitor, and have explained its catalytic mechanism. Future
research lines focus on deciphering the role of Autotaxin isoforms,
its mode of regulation, and the role of cell-surface interactions
in its activity.
- JBP1 is the protein that bind the unusual base J in parasites,
and is homologous to the TET proteins involved in myeloid leukemia.
We are focusing to understand how JBP1 acts to amplify base J in
specific regions in the genome of parasites, and understanding the
structure of the thymidine hydroxylation function, which is
homologous between JBPs and TET proteins.
- Geminin and its homologues Idas and GemC1 are coiled coil
proteins involved in DNA replication licensing, making sure that
exactly only one copy of the DNA is made during that massively
parallel process . We try to understand how complexes between these
proteins affect the function of Geminin in proliferation -
differentiation decisions in cells, especially in modulating the
interaction with Cdt1, a master regulation of replication
- Mitotic kinases like Plk1-3, Mps1, BubR1 and Bub1, regulate the
mitotic check point in various ways, making sure that only one copy
of each chromatid goes in each daughter cell after cell division
(mitosis). We are most interested to how the regulatory domains of
these kinases, PDB and TPR domains, spatiotemporally regulated the
various functions of these proteins, facilitating interactions with
other proteins in the cell and regulating the activity of the