How electrostatic interactions drive nucleosome binding of RNF168 & PSIP : structural studies and their implications for rational drug design

Abstract

The studies presented in the work show the potential of

the integrative use of biophysical data in defining the structural basis of protein interactions.

Even if the results obtained hold a degree of ambiguity, this approach allows to

iteratively refine and validate the model and interpret its meaning for the molecular basis of protein function. Often all three points at the same time. This dynamic nature makes the use of structural models in the design of therapeutic compounds especially useful since the inhibition of a certain protein function might not require a structure to be accurate down to the last atom but rather highlight key interactions or structural features that can be addressed in context of small molecule or peptide inhibitors. Presented are the use of strucutral biochemistry techniques to investigate the mechanism of how the ubiquitine ligase PSIP1 obtains its target specificity. Furthermore, another epigenetic effector protein PSIP1 is investigated with the aim to develop a workflow for the design of potential peptide-based inhibitors.