Saturday, February 18, 2017
Exhibit Hall (Hynes Convention Center)
Robert Shaffer, Boston University, Boston, MA
Protein-protein interaction sites, or PPIs, are typically large and flat, and are often considered undruggable. This is because they do not fit the classic criterion of having a substantial pocket for small molecule drugs to bind. It is estimated that there are between 40,000 and 200,000 PPI’s in the interactome. In order to exploit this vast space of potential drug targets, we need to better understand PPI’s and in particular their structural dynamics. A class of proteins called scaffold proteins functions by orienting its protein binding partners so as to enable or enhance their function. Also, it has been shown that mutations outside of protein binding sites can affect binding, so scaffold activation may well be allosteric. However, the molecular mechanisms underlying these scaffold-dependent activation processes are poorly understood. The goal of the proposed work is to test the hypothesis that scaffold proteins undergo specific ligand-induced conformational changes, in order to actively bring the bound proteins into the close proximity required for their activities. To achieve this goal, I will analyze ligand-induced conformational changes. This work will lead to an improved understanding of the conformational dynamics of scaffold proteins, and may ultimately lead to drug discovery efforts targeting novel allosteric druggable sites that avoid “undruggable” flat planar PPI sites. As a test system, I will use the intracellular scaffold protein NF-κB essential modulator (NEMO), a component of the Inhibitor of κB Kinase (IKK) complex, which is a key control point in NF-κB signaling. NEMO has been shown to have disordered regions, and to exist in multiple oligomeric states, particularly as a constitutive noncovalent dimer. I am particularly interested in the role that the yet uncharacterized region of NEMO extending from residue 110 to 195 might play in NEMO-IKKβ binding, based on preliminary data showing that NEMO 44-195 binds IKKβ more strongly than NEMO 1-120, and on the functions of disease-associated mutations that fall in this highly conserved region.