Roman Osman, PhD

Type I MAGE proteins interact witha RING protein Kap1 (a ubuquitin ligase) through a conserved MAGE homology domain (MHD) that contains two winged helix (WH1 and 2) motifs. X-ray structures show that the WH2 domain exposes the binding site for the RING protein during a conformational change from the free to the bound state. MD simulations of the MAGE-A3 MHD in the closed and open forms demonstrate a hinge region between the WH domains that allows the conformational change to the open form that binds Kap1. Our MD studies also show several structural pockets with unique physicochemical properties that could potentially accommodate small molecules that may prevent the conformational transition of WH2 and arrest the MHD in the closed conformation. In this form MAGE-A3 cannot interact with the RING protein Kap1 and thus induce apoptosis in multiple myeloma cells. We have used the closed form of MAGE-A3 to conduct an in silico screen on large and chemically diverse libraries and discovered at least three small molecules that interact with MAGE-A3 and induce apoptosis of myeloma cells. In collaboration with Dr. Opher Giladi from Oxford, England we have determined the structure of MAGE A3 at 2.07 Å resolution. This structure has been used to conduct MD simulation to determine the binding affinity and the sites of interaction with the small ligands we identified. In collaboration with Hearn Jay Cho  we are evaluating the activity of these compounds against multiple myeloma cell lines to determine which ones are suitable leads for further development as MAGE-targeted agents.