Fri, Nov. 7, 2014, 4:30pm - 6:00pm
Frick Chemistry Laboratory, Taylor Auditorium
Host: Tom Muir
Targeting Protein-Protein Interactions
Protein-protein interactions (PPIs) are essential to vital cellular processes, but are also involved in numerous pathophysiological states and serve as potential targets for therapeutic intervention. An interesting class of PPIs is the one involving PDZ domains, that function as scaffolding proteins that are involved in assembling large protein complexes in the cell. First part of the talk will focus on identifying inhibitors the PSD-95/NMDA receptor interaction, where we have used peptides as templates. In particular, we have exploited the fact that PSD-95 contains two tandem PDZ domains, PDZ1-2 and we designed and synthesized a range of dimeric inhibitors, which resulted in dramatic increases in both affinity and stability (ACIE 2009). We have redesigned these inhibitors and have elucidated the structural details of their binding mechanism using X-ray crystallography, NMR and small-angle X-ray scattering (SAXS) (PNAS 2012). The redesigned inhibitors were also investigated in vivo and found promising effects in a model of stroke in mice (PNAS 2012), as well as in models of inflammatory pain (Neuropharmacol. 2013).
The second part of the talk discusses backbone hydrogen bond interactions in protein-protein interactions using PDZ domains as example, where several backbone H-bond interactions are of key importance. We have employed amide-to-ester mutations in peptide ligands (JACS 2013) and proteins (Nature Commun 2014) to elucidate the molecular details of how PDZ domains bind the C-terminal peptide ligands. In the third and final part of the talk discusses how the principle of dimeric peptide based ligands has been exploited to other signaling pathways and proteins. Specifically the key interaction in inhibitory synapses between the scaffolding protein gephyrin and glycine/GABA receptors has been explored and potent peptide-based ligands have been designed and applied (Nature Commun, in press).