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Cell. 2019 Jun 13;177(7):1725-1737.e16. doi: 10.1016/j.cell.2019.04.006. Epub 2019 May 9.

Cryo-EM Structure of Chikungunya Virus in Complex with the Mxra8 Receptor.

Author information

1
Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
2
Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
3
Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
4
PaxVax, San Diego, CA 92121, USA.
5
Department of Chemistry, Washington University, Saint Louis, MO 63110, USA.
6
Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: diamond@wusm.wustl.edu.
7
Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: fremont@wustl.edu.

Abstract

Mxra8 is a receptor for multiple arthritogenic alphaviruses that cause debilitating acute and chronic musculoskeletal disease in humans. Herein, we present a 2.2 Å resolution X-ray crystal structure of Mxra8 and 4 to 5 Å resolution cryo-electron microscopy reconstructions of Mxra8 bound to chikungunya (CHIKV) virus-like particles and infectious virus. The Mxra8 ectodomain contains two strand-swapped Ig-like domains oriented in a unique disulfide-linked head-to-head arrangement. Mxra8 binds by wedging into a cleft created by two adjacent CHIKV E2-E1 heterodimers in one trimeric spike and engaging a neighboring spike. Two binding modes are observed with the fully mature VLP, with one Mxra8 binding with unique contacts. Only the high-affinity binding mode was observed in the complex with infectious CHIKV, as viral maturation and E3 occupancy appear to influence receptor binding-site usage. Our studies provide insight into how Mxra8 binds CHIKV and creates a path for developing alphavirus entry inhibitors.

KEYWORDS:

HDX mass spectrometry; alphavirus; cryo-electron microscopy; infection; protein crystallography; surface plasmon resonance; virus receptor

PMID:
31080061
DOI:
10.1016/j.cell.2019.04.006

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