Ricerc@Sapienza

The Measles, Nipah and Hendra viruses (MeV, NiV, HeV) are severe human pathogens members of the Paramyxovirinae sub-family within the family of Paramyxoviridae. MeV, NiV and HeV have a single stranded, non-segmented, RNA genome that is enveloped by the nucleoprotein (N) in a helical nucleocapsid. The RNA- dependent RNA polymerase (RdRp) is composed of the large (L) protein and the phosphoprotein (P). The N protein consists of a structured N-terminal domain (NCORE) that binds the genome, and a C-terminal disordered domain (NTAIL) exposed at nucleocapsid surface. In the three viruses, NTAIL binds to the C- terminal X domain (PXD) of the P protein leading the recruitment of the polymerase complex on the genome. The NTAIL domain contain a short, order-prone molecular recognition element (alpha-MoRE) that, upon the binding with XD, undergoes a disorder-to-order transition. The regions of NTAIL flanking the alpha-MoRe remains disordered also in the bound form and they are called "fuzzy" regions. Recent studies showed that the fuzzy region in MeV affects, decreasing, both the binding affinity between NTAIL and PXD and the folding rate of the alpha-MoRE after the binding.
NTAIL represents an extremely attractive target for the perspective of developing pharmaceutical strategies able to inhibit its interaction with PXD to interrupt the life cycle of the viruses. This research project aims to perform a characterization of the folding upon binding mechanism between NTAIL and XD and to unveil the role of disorder in this process. The informations obtained by these studies could be used to design a pharmacophore able to inhibit the interaction between PXD and NTAIL.