BMERC Seminar: Promiscuity in regulatory proteins such as PD-1 hinder their druggability


December 4th, 2016

When:       Thursday, December 8, 10:30 am

Where:      ENG room 203, 44 Cummington Street

Title:          Promiscuity in regulatory proteins such as PD-1 hinder their druggability

Speaker:  Prof. Carlos J. Camacho

Department of Computational and Systems Biology

University of Pittsburgh

Abstract:  Many regulatory proteins use structural flexibility to bind specifically to multiple partners. Although conformational selection and induced fit offer alternative pathways to rationalize multi-ligand binding, in practice we lack a structural understanding of how nature designs a flexible binding interface to select some ligands, but not others. Using molecular dynamics simulations (MDS) to identify the molecular interactions responsible for this “selective promiscuity”, I will show that promiscuity can be triggered by ligand-specific motifs that activate induced fit binding pathways toward different bound-like receptor states. This is the case for PD-1, a recent breakthrough anti-cancer immunotherapy target. Collectively, our studies provide insight pertinent to the structural basis and evolution of selective promiscuity in flexible regulatory proteins. Our findings also suggest a biophysical approach to exploit innate binding pathways to improve the druggability of seemingly undruggable targets.