FOR 806:  Interfering with Intracellular Protein-protein Interactions - Probing Protein Functions with Small Molecules

• Subject Area: Medicine
• Term: from 2007 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 29078704

The assorted flow of information within cellular pathways largely relies on reversible and specific protein-protein interactions. In many instances, they often involve extended, relatively flat protein surfaces, which cannot easily be blocked by small molecules. Therefore, pharmacological interference by targeting intracellular protein-protein interactions is an especially demanding task, requiring research at the interface of molecular biology and chemistry.
To accomplish this goal, intracellular protein-protein interactions will be characterised functionally, structurally and kinetically in vitro and in vivo within the framework of the Research Unit. The information obtained, combined with structurally guided in silico-strategies, will set the stage for the identification of protein interfaces, at which pharmacological intervention appears feasible, and for the subsequent identification of interfering small molecules that either disrupt or mimick a given protein-protein interaction. The functional consequences, selectivity and potency of pharmacological interference with a given protein-protein interaction will be examined in vivo, mainly on the cellular level (proof of concept).
Aims of the research activity are
(1) to determine the functional contribution(s) of a protein-protein interaction and
(2) to develop chemical tools to study protein interactions systematically. It is envisaged that a chemical biology approach at the level of protein-protein interaction interfaces may extend the molecular basis of drug therapy in both qualitative and quantitative terms.

• DFG Programme: Research Units

Projects

• Administration and central services (Applicant Oschkinat, Hartmut )
• Design, synthesis and functional characteristics of low molecular weight proline-rich motif (PRM) mimetics recognized by PRM binding domains (Applicants Beyermann, Michael ;  Kühne, Ronald ;  Schmalz, Hans-Günther )
• Functional analysis of cell signaling events following inhibition of clathrin/ AP2-mediated endocytosis (Applicant Haucke, Ph.D., Volker )
• GYF domain mediated protein: protein interactions (Applicant Freund, Christian )
• Interfering with protein interaction of phosphoinositide-3-kinase gamma and of store-operated calcium channels (Applicant Schaefer, Michael )
• Interfering with protein-protein interactions in the spliceosme (Applicants Lührmann, Reinhard ;  Wahl, Markus C. )
• Modulation of PDZ domain-mediated protein-protein interactions (Applicant Oschkinat, Hartmut )
• Perturbance of enzyme function by blocking dimer interface formation: Novel route to specific antibiotics (Applicant Klebe, Gerhard )
• Protein-protein interaction in the mammalian circadian system (Applicant Kramer, Achim )
• Protein-protein interactions during cell-cycle control: The human oncoprotein gankyrin and GADD45gamma (Applicant Heinemann, Udo )
• Small molecular weight interfering substances of the Met-Gab1 and the Wnt-ß-catenin signaling pathways (Applicant Birchmeier, Walter )
• Synthesis, screening and crystallization of small molecules targeting protein-protein interactions (Applicant Rademann, Jörg )
• The function of AKAP-dependent protein-protein interactions in the regulation of vasopressin-mediated water reabsorption and cardiac myocyte contractility (Applicant Klußmann, Enno )

• Spokespersons: Professor Dr. Christian Freund; Professor Dr. Hartmut Oschkinat