The Invisible Protein States of Mdmx and Mdm2 Determine Ligand-Binding Affinity Revealed by Crystallographic Structures and NMR Dynamics

Abstract

Overexpression of Mdm2/MdmX is highly related to cancer occurrence and development. Mdm2 and MdmX are highly homologous and Mdm2 inhibitors exhibit weak affinity for MdmX. It is fundamentally interesting to understand how Mdm2 and MdmX distinguish the binding affinity of the same ligand. Previously, we have identified three flexible regions on N-MdmX that defined an invisible state, facilitated by NMR study (Qin et al. Biochemistry 2017, 56, 44, 5943-5954). Recently we solved five X-ray crystallographic structures of Mdm2/nutlin-3a complexes (5ZXF and 5Z02) and MdmX/nutlin-3a complexes (7C3Q, 7C44 and 7C3Y).