I am interested in understanding the spatiotemporal control that small domains exert on their ‘host’ protein at the level of the molecular structures and interactions. Concurrently, my group is developing methods to help the wider scientific community study macromolecules more efficiently by X-ray crystallography.We are currently analyzing the regulatory mechanisms of a number of multi-domain enzymes involved in diverse biological processes by studying their molecular structures and its relationship with their biophysical and biochemical properties. For example, autotaxin (ATX), which is a phosphodiesterase that produces the signaling lipid LPA, is a promising drug target in diseases such as fibrosis, arthritis, neuropathic pain and cancer. Our group has determined the structure of ATX, and together with other groups at the NKI we have helped develop highly specific and potent inhibitors. Our aim now is to find out how the regulatory domains of ATX modulate its interaction with integrins, LPA receptors and heparin at the cell surface, and thereby regulate its function. We are also interested in the regulatory domains of the Polo kinases and of the Bub1, BubR1 and Mps1 kinase network, which are critical components required for cell division. Understanding the structural basis for substrate recognition by these domains (PBD and TPR domains respectively) is important for developing small molecule inhibitors that can specifically block their function.Our other main interest is in developing automated methods to build macromolecular models more accurately and efficiently from X-ray crystallography data. We have a long-term commitment to the ARP/wARP software suite, which we originally developed for automated model building. A new focus for the lab is the PDB_REDO project, aiming to update existing models in the world wide protein data bank (wwPDB), as well as helping scientists deposit better models. Here we can capitalize on our knowledge and experience in model-building tools to provide the crystallographic software and decision-making frameworks needed to rebuild and refine crystallographic macromolecular structures.