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Highlight | Structural biology
IBS researchers [collaboration] reveail in the measles virus a molecular mechanism that could constitute a new target to treat its infection, or even that of other viruses of the same family which are highly dangerous human pathogens.
A team at the ‘Institut de Biologie Structurale’ (CEA/CNRS/UGA), in collaboration with the CIRI (Inserm/CNRS/ENS de Lyon/UCBL), discovered a novel interaction between two proteins from the measles virus. This ultra-weak interaction, involving only four amino acids situated in a very flexible and dynamic protein region, is essential for measles virus replication. This newly discovered interaction constitutes a new target to treat measles infection, but also infection by other viruses from the same family, that comprises highly dangerous human pathogens.
These results are published in Science Advances, on August 22nd, 2018..
The measles virus genome is covered by numerous copies of the ‘nucleoprotein’, forming a very long and protective helicoid structure. This envelope of the genome is essential for viral replication and is controlled by the ‘phosphoprotein’. This latter protein contains a surprising fraction of conformational disorder, meaning that it lacks a well-defined structure. The first 300 amino acids of the phosphoprotein are indeed disordered and highly flexible.
The function of these disordered domains remains elusive, in particular in view of the parsimonious use of genetic information by this family of viruses. Scientists at the IBS used high resolution nuclear magnetic resonance spectroscopy to show that this area of the amino acid chain of the phosphoprotein contains two nucleoprotein-interaction sites at the opposite ends of the disordered domain. These two interaction sites work together to maintain the nucleoprotein in a form that facilitates viral replication. In fact, mutation of only four amino acids in the newly discovered second interaction site, which interacts very weakly, inhibits measles virus replication.
“This interactions site constitutes a new target for treating measles virus infection or infection by other dangerous human viruses”, emphasizes Martin Blackledge, CEA research director and corresponding author (With Rob Ruigrok, UGA) of this study. In fact, this essential mechanism seems to be conserved among Paramyxoviruses, the family to which measles virus, but also mumps and Nipah viruses, belong. “All of these viruses contain this kind of disordered domains and our observations open up new perspectives for the development of drugs against this family of pathogens”, adds M. Blackledge.
Scheme of the viral replication mechanism influenced by the expression or inhibition of the ultra- weak interaction.
Measles virus nucleocapsid (top view).
© Gutsche I, Desfosses A, Effantin G, Ling WL, Haupt M, Ruigrok RWH, Sachse C, Schoehn G.
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.