X-ray crystallography is fundamental to our understanding of matter in chemistry and (molecular) biology. Many properties and interactions of molecules depend on their three-dimensional atomic structure. X-ray crystallography can resolve molecular structures to atomic resolution and is applicable to molecules and assemblies ranging in size from a few to thousands of atoms in organic, organometallic, inorganic and pharmaceutical compounds, to molecules containing 10 to 100 thousand atoms in large bio-molecules and bio-molecular assemblies like viruses and ribosomes. Our research group works along three main lines at the international forefront of structural biology and structural chemistry. Our main focus is to understand molecular recognition and regulation in biomedical processes, such as the arrest of bleeding, infection and immunity. Structural data are critical: they provide detailed insights into the precise molecular interactions responsible for recognition and reveal the (sometimes substantial) structural changes upon complex formation associated with molecular regulation. Insights into these complex and detailed interactions are paramount to understanding the molecular mechanisms underlying the protein interaction networks and bio-complexity and to the development of novel therapeutic compounds. As a service for synthetic chemists we perform state-of-the-art single crystal structure determinations and their interpretation. This is essential for the full understanding of the structural chemistry on a molecular level. Additionally, as a service for protein scientists we offer protein crystallization for the determination of the crystal structure. Finally, we develop a data-integration method based on the description of the diffraction process with physical parameters.
The research group of prof. dr. Piet Gros studies bio-molecular recognition and regulation processes with emphasis on medically important proteins in and on (human) cell membranes and in the surrounding fluids. Regulation in cells and organisms is achieved by the interplay of proteins acting in concert to achieve a control over time and space. In many cases, the proteins involved are composed of multiple domains and form multi-protein complexes. This enables a collective set of proteins to form a machinery that carries out elementary regulatory and signaling functions such as initiation, amplification, localization and inhibition. Our primary goal is to reveal the molecular mechanisms that underlie the recognition and regulation processes. The methods we use include mammalian (membrane) protein expression, purification and biochemical/biophysical characterizations, crystallography, which are complemented by e.g. mass spectrometry, fluorescence and cryo-EM where we collaborate with colleagues.
Research of dr. Eric Huizinga: An essential first step in the arrest of bleeding is the adhesion of blood platelets to a damaged vessel wall. In this process the large multimeric glycoprotein von Willebrand Factor (VWF) functions as a bridge between blood platelets and collagen fibers exposed at sites of vascular damage. A fascinating aspect of VWF is that it has no significant interaction with platelets in the absence of vascular damage, but binds platelets rapidly once VWF becomes immobilized at sites of vascular damage or is exposed to high shear stress. In a long-standing collaboration with the Thrombosis and Haemostasis Laboratory of the University Medical Center Utrecht we study the structural basis of von Willebrand factor mediated platelet adhesion. We solved the crystal structure of the collagen-binding A3 domain of von Willebrand factor and mapped the position of its collagen-binding site by a combination of co-crystallisation with an inhibiting antibody and site-directed mutagenesis.
The group of dr. Bert Janssen focusses on structural neurobiology. Communication between cells in our brain is critical for its development and function. This cross-talk is most often mediated by proteins. We are interested in how protein signaling systems initiate and transduce signals between cells in our central nervous system. Work in the group centres on elucidating molecular mechanisms that underlie intercellular signaling between glia cells and neurons. Two systems important for the function and repair of the nervous system are currently the focus of our research; 1. The myelin inhibitors and their receptors in nervous system repair inhibition and 2. Signaling mechanisms of proneurotrophic factors and their receptors in nervous system cell death. We use mammalian protein expression systems, protein crystallography and biochemical, biophysical and cellular techniques to get detailed understanding of how these systems work.
Dr. Martin Lutz is head of The National Single Crystal X-ray Facility at Utrecht University which offers crystal structure determinations to synthetic chemists at universities, institutes and companies in The Netherlands. Examples of our structural studies include model systems that mimic catalytic sites in proteins or synthetic catalysts to be used in the clean production of desired pharmaceuticals or materials. Such studies are necessary for a detailed understanding of the catalytic process at the molecular level. Similarly, crystal structures of pharmaceuticals are studied to obtain experimental evidence of molecular conformations, intermolecular interactions, absolute configuration, polymorphs and details of solvent inclusions. This information is needed as guidance to develop better pharmaceuticals. Supramolecular structures of self-organizing molecules through intermolecular interactions are studied as part of research aiming at the development of desired new materials.
The research of dr. Loes Kroon-Batenburg focusses on the development of methods for accurate integration of diffraction data. All methods are implemented in the software suite EVAL. Recently we started working on data collection and data processing of less orderedly packed crystals. Such crystals give rise to diffuse scattering. We will develop measurement strategies and algorithms for data processing and interpretation of the diffuse scattering and for computing diffuse scattering from protein crystal structures. The diffuse scattering of crystals in between Bragg peaks is commonly ignored. However, these intensities are affected by so-called thermal diffuse scattering. Therefore, even the derived average structure is not fully accurate. She is working towards probing internal dynamics of macromolecules from the diffuse scattering.