Protein Sample Production Facility

In close co-operation with the Helmholtz-Zentrum für Infektionsforschung (HZI) in Braunschweig, we operate the Helmholtz Protein Sample Production Facility (Helmholtz PSPF). The PSPF offers expertise in protein production and biophysical characterization for structural biology to external and internal partners, using various host systems tailored to specific experimental requirements. On the technical side, the PSPF has a focus on the production of transient and other non-covalent protein-protein complexes. The Helmholtz PSPF offers an ideal opportunity to set up collaborative projects on topics that are initially outside the area of expertise of the Heinemann laboratory. Frequently, these co-operations yield crystal structures and molecular insight on proteins linked to human disease or target proteins for pharmacological intervention with small molecules. Recently, a collaboration with the laboratory of Ludwig Thierfelder has yielded the crystal structure of a mutant form of the desmosomal protein plakophilin-2 that is linked to arrhythmogenic right ventricular cardiomyopathy. In collaboration with the laboratories of Hartmut Oschkinat and Jörg Rademann (both Leibniz-Institut für Molekulare Pharmacology, Berlin) the binding of small-molecule ligands to the PDZ domains of the proteins Shank3 from the postsynaptic density region and Dishevelled-3 involved in Wnt signaling was studied by high-resolution crystallographic analysis. It could be shown that ligand binding to both PDZ domains follows similar principles, and a foundation for the design of ligands binding with higher affinity was provided.

Binding

a) Zoom into the binding pocket; hydrogen bonds between 36 and the Shank3 PDZ carboxylate binding loop (light blue) are represented by dashed lines. b) Surface representation of the binding pocket; hydrophobic residues are colored in yellow, while basic and acidic residues are shown in blue and red, respectively.


Figure adapted from

Saupe, J., Roske , Y., Schillinger, C., Kamdem, N., Radetzki, S., Diehl, A., Oschkinat, H., Krause, G., Heinemann, U., Rademann, J.
Discovery, structure-activity relationship studies, and crystal structure of nonpeptide inhibitors bound to the Shank3 PDZ domain
Chem. Med. Chem. (2011) 6, 1411-1422.