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Published on: January 5, 2017
Crystal structure of two CD46 domains reveals an extended measles virus-binding surface
J M Casasnovas1, M Larvie, T Stehle
1Department of Biosciences at NOVUM, Karolinska Institute, 14157 Huddinge, Sweden.
Abstract:
Measles virus is a paramyxovirus which, like other members of the family such as respiratory syncytial virus, is a major cause of morbidity and mortality worldwide. The cell surface receptor for measles virus in humans is CD46, a complement cofactor. We report here the crystal structure at 3.1 A resolution of the measles virus-binding fragment of CD46. The structure reveals the architecture and spatial arrangement of two glycosylated short consensus repeats with a pronounced interdomain bend and some flexibility at the domain interface. Amino acids involved in measles virus binding define a large, glycan-free surface that extends from the top of the first to the bottom of the second repeat. The extended virus-binding surface of CD46 differs strikingly from those reported for the human virus receptor proteins CD4 and intercellular cell adhesion molecule-1 (ICAM-1), suggesting that the CD46 structure utilizes a novel mode of virus recognition. A highly hydrophobic and protruding loop at the base of the first repeat bears a critical virus-binding residue, thereby defining an important recognition epitope. Molecules that mimic the conformation of this loop potentially could be effective anti-viral agents by preventing binding of measles virus to CD46.
Insights
Researchers determined the measles virus CD46 receptor structure, revealing a novel binding mechanism. This discovery could lead to new antiviral therapies targeting measles virus entry.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- Measles virus causes significant global morbidity and mortality.
- CD46 serves as the human cell surface receptor for measles virus.
- Understanding virus-receptor interactions is crucial for developing antiviral strategies.
Purpose of the Study:
- To elucidate the crystal structure of the measles virus-binding fragment of CD46.
- To characterize the molecular details of measles virus recognition by CD46.
- To identify potential targets for novel antiviral agents.
Main Methods:
- X-ray crystallography was used to determine the structure of the CD46 fragment at 3.1 A resolution.
- Analysis of the protein structure to identify key amino acids and surface features involved in virus binding.
Main Results:
- The crystal structure revealed the architecture of two glycosylated short consensus repeats in CD46.
- A large, glycan-free surface involved in measles virus binding was identified, extending across both repeats.
- A critical virus-binding epitope was located on a hydrophobic loop at the base of the first repeat.
Conclusions:
- The CD46 structure presents a novel mode of virus recognition compared to other known viral receptors.
- The identified virus-binding surface and epitope offer potential targets for therapeutic intervention.
- Mimicking the conformation of the critical loop could lead to effective anti-measles virus agents.
