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Published on: December 1, 2011
Molecular Basis of Arthritogenic Alphavirus Receptor MXRA8 Binding to Chikungunya Virus Envelope Protein
Hao Song1, Zhennan Zhao2, Yan Chai3
1Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.
Abstract:
Arthritogenic alphaviruses, such as Chikungunya virus (CHIKV), cause severe and debilitating rheumatic diseases worldwide, resulting in severe morbidity and economic costs. Recently, MXRA8 was reported as an entry receptor. Here, we present the crystal structures of the mouse MXRA8, human MXRA8 in complex with the CHIKV E protein, and the cryo-electron microscopy structure of human MXRA8 and CHIKV virus-like particle. MXRA8 has two Ig-like domains with unique structural topologies. This receptor binds in the "canyon" between two protomers of the E spike on the surface of the virion. The atomic details at the interface between the two binding entities reveal that both the two domains and the hinge region of MXRA8 are involved in interaction with CHIKV E1-E2 residues from two protomers. Notably, the stalk region of MXRA8 is critical for CHIKV virus entry. This finding provides important information regarding the development of therapeutic countermeasures against those arthritogenic alphaviruses.
Insights
Chikungunya virus (CHIKV) uses the MXRA8 receptor for cell entry. Structural studies reveal MXRA8 binds CHIKV
Area of Science:
- Virology and Structural Biology
- Molecular mechanisms of viral entry
Background:
- Arthritogenic alphaviruses, including Chikungunya virus (CHIKV), cause significant global morbidity and economic burden due to rheumatic diseases.
- MXRA8 has recently been identified as a critical cellular entry receptor for CHIKV.
- Understanding the molecular interactions between CHIKV and MXRA8 is crucial for developing antiviral therapies.
Purpose of the Study:
- To elucidate the structural basis of CHIKV binding to its receptor, MXRA8.
- To provide atomic-level insights into the interaction interface for therapeutic target identification.
Main Methods:
- X-ray crystallography was employed to determine the structures of mouse MXRA8, human MXRA8 complexed with CHIKV E protein, and CHIKV virus-like particles bound to human MXRA8.
- Cryo-electron microscopy provided high-resolution structural data of the MXRA8-CHIKV complex.
Main Results:
- MXRA8 possesses two Ig-like domains with distinct structural topologies.
- The receptor binds within a 'canyon' formed by CHIKV E protein protomers on the virion surface.
- Atomic interactions involve both MXRA8 domains and hinge region with CHIKV E1-E2 residues, and the stalk region is vital for viral entry.
Conclusions:
- The detailed structural understanding of the MXRA8-CHIKV interaction provides a foundation for designing targeted antiviral strategies.
- Identifying the critical role of the MXRA8 stalk region offers a new avenue for therapeutic intervention against CHIKV and related alphaviruses.
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